Genes associated with mechanical stress, expression products therefrom, and uses thereof

ABSTRACT

The disclosure relates to mechanical stress induced genes, such as those from human and from mice, probes therefor, tests to identify such genes, expression products of such genes, uses for such genes and expression products, e.g., in diagnosis (for instance risk determination), treatment, prevention, or control, of osteoporosis or factors or processes which lead to osteoporosis; and, to diagnostic, treatment, prevention, or control methods or processes, as well as compositions therefor and methods or processes for making and using such compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority of U.S. patent applicationSer. No. 09/729,485 filed Dec. 4, 2000 which claims the priority of U.S.Provisional application Ser. No. 60/207,821, filed May 30, 2000 and U.S.Ser. No. 09/632, 862, filed Aug. 4, 2000.

[0002] Reference is also made to U.S. Provisional application Ser. No.60/084,944, filed May 11, 1998; and the full U.S. utility application,Ser. No. 09/309,862, filed May 11, 1999, and claiming priority from U.S.Provisional application Ser. No. 60/084,944 (herein “the May 14, 1999Einat et al. full U.S. utility application”); and U.S. Ser. No.09/312,216, filed, May 14,1999; and U.S. Provisional application Ser.No. 60/085,673, filed May 15, 1998; U.S. Provisional application Ser.No. 60/085,673, filed May 15, 1998; U.S. Provisional application Ser.No. 60/207, 821, filed May 30, 2000; U.S. Ser. No. 09/312,216, filed,May 14, 1999; U.S. Provisional application Ser. No. 60/084,944; and theMay 11, 1999 Einat et al. full U.S. utility application; as well as eachdocument or reference cited in these applications, are hereby expresslyincorporated herein by reference. Documents or references are also citedin the following text and, each of these documents or references(“herein-cited documents or references”), as well as each document orreference cited in each of the herein-cited documents or references, arehereby expressly incorporated herein by reference. It is explicitlystated that the inventive entity of the May 11, 1999 Einat et al. fullU.S. utility application is not another or others as to the inventiveentity of this application; and, that the inventive entity of thepresent application is not another or others as to the inventive entityof the May 11, 1999 Einat et al. full U.S. utility application.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0003] Not Applicable.

FIELD OF THE INVENTION

[0004] This invention relates to mechanical stress induced genes, probestherefor, tests to identify such genes, expression products of suchgenes, uses for such genes and expression products, e.g., in diagnosis(for instance risk determination), treatment, prevention, or control, ofosteoporosis or factors or processes which lead to osteoporosis,osteopenia, osteopetrosis, osteoscierosis, osteoarthritis, periodontosisand bone fractures; and, to diagnosis, treatment, prevention, or controlmethods or processes, as well as compositions therefor and methods orprocesses for making and using such compositions.

BACKGROUND OF THE INVENTION

[0005] Bone is composed of a collagen-rich organic matrix impregnatedwith mineral, largely calcium and phosphate. Two major forms of boneexist, compact cortical bone forms the external envelopes of theskeleton and trabecular or medullary bone forms plates that traverse theinternal cavities of the skeleton. The responses of these two forms tometabolic influences and their susceptibility to fracture differ.

[0006] Bone undergoes continuous remodeling (turnover, renewal)throughout life. Mechanical and electrical forces, hormones and localregulatory factors influence remodeling. Bone is renewed by two opposingactivities that are coupled in time and space. Parfitt (1979) Calcif.Tis. Int. 28:1-5. These activities, resorption and formation, arecontained within a temporary anatomic structure known as abone-remodeling unit. Parfitt (1981) Res. Staff Physic. Dec.:60-72.Within a given bone-remodeling unit, old bone is resorbed byosteoclasts. The resorbed cavity created by osteoclasts is subsequentlyfilled with new bone by osteoblasts, synthesizing bone organic matrix.

[0007] Peak bone mass is mainly genetically determined, though dietaryfactors and physical activity can have positive effects. Peak bone massis attained at the point when skeletal growth ceases, after which timebone loss starts.

[0008] In contrast to the positive balance that occurs during growth, inosteoporosis, the resorbed cavity is not completely refilled by bone.Parfitt (1988) in, Osteoporosis: Etiology, Diagnosis, and Management(Riggs and Melton, eds.) Raven Press, New York, pp. 74-93. Osteoporosis,or porous bone, is a progressive and chronic disease characterized bylow bone mass and structural deterioration of bone tissue, leading tobone fragility and an increased susceptibility to fractures of the hip,spine, and wrist (diminishing bone strength).

[0009] Bone loss occurs without symptoms. The Consensus DevelopmentConference ((1993) Am. J. Med. 94:646-650) defined osteoporosis as “asystemic skeletal disease characterized by low bone mass andmicroarchitectural deterioration of bone tissue, with a consequentincrease in bone fragility and susceptibility to fracture.”

[0010] Common types of osteoporosis include postmenopausal osteoporosis;and senile osteoporosis, which generally occurs in later life, e.g.,70+years. See, e.g., U.S. Pat. No. 5,691,153. Osteoporosis is estimatedto affect more than 25 million people in the United States (Rosen (1997)Calcif. Tis. Int. 60:225-228); and, at least one estimate asserts thatosteoporosis affects 1 in 3 women. Keen et al. (1997) Drugs Aging11:333-337. Moreover, life expectancy has increased, and in the westernworld, 17% of women are now over 50 years of age; and, a woman canexpect to live one third of her life after menopause. Thus, someestimate that 1 out of every 2 women and 1 out of 5 men will eventuallydevelop osteoporosis; and, that 75 million people in the U.S., Japan andEurope have osteoporosis. The World Summit of Osteoporosis Societiesestimates that more than 200 million people worldwide are afflicted withthe disease. The actual incidence of the disease is difficult toestimate since the condition is often asymptomatic until a bone fractureoccurs. It is believed that there are over 1.5 millionosteoporosis-associated bone fractures per year in the U.S. Of these,300,000 are hip fractures that usually require hospitalization andsurgery and may result in lengthy or permanent disability or even death.Spangler et al. “The Genetic Component of Osteoporosis Mini-review”; andhttp://www.csa.com.osteointro.html).

[0011] Osteoporosis is also a major health problem in virtually allsocieties. Eisman (1996); Wark (1996) Maturitas 23:193-207; and U.S.Pat. No. 5,834,200. There is a 20-30% mortality rate related to hipfractures in elderly women (U.S. Pat. No. 5,691,153); and, such apatient with a hip fracture has a 10-15% greater chance of dying thanothers of the same age. Further, although men suffer fewer hip injuriesthan women, men are 25% more likely than women to die within one year ofthe injury. See Spangler et, al., supra. Also, about 20% of the patientswho lived inependently before a hip fracture remain confined in along-term health care facility one year later. The treatment ofosteoporosis and related fractures costs over $10 billion annually.

[0012] Osteoporosis treatment helps stop further bone loss andfractures. Common therapeutics include HRT (hormone replacementtherapy), bisphosphonates, e.g., alendronate (Fosamax), estrogen andestrogen receptor modulators, progestin, calcitonin, and vitamin D.While there may be numerous factors that determine whether anyparticular person will develop osteoporosis, a step towards prevention,control or treatment of osteoporosis is determining whether one is atrisk for osteoporosis. Genetic factors also play an important role inthe pathogenesis of osteoporosis. Ralston (1997); see also Keen et al.(1997); Eisman (1996); Rosen (1997); Cole (1998); Johnston et al. (1995)Bone 17(2 Suppl)19S-22S; Gong et al. (1996) Am. J. Hum. Genet.59:146-151; and Wasnich (1996) Bone 18(3 Suppl):179S-183S. Someattribute 50-60% of total bone variation (bone mineral density; BMD),depending upon the bone area, to genetic effects. Livshits et al. (1996)Hum. Biol. 68:540-554. However, up to 85%-90% of the variance in bonemineral density may be genetically determined.

[0013] Studies have shown from family histories, twin studies, andracial factors, that there may be a predisposition for osteoporosis.Jouanny et al. (1995) Arthritis Rheum. 38:61-67; Garnero et al. (1996)J. Clin. Endrocrinol. Metab. 81:140-146; Cummings (1996) Bone 18(3Suppl):165S-167S; and Lonzer et al. (1996) Clin. Pediatr. 35:185-189.Several candidate genes may be involved in this, most probablymultigenic, process.

[0014] Cytokines are powerful regulators of bone resorption andformation under control of estrogen/testosterone, parathyroid hormoneand 1,25(OH)2D3. Some cytokines primarily enhance osteoclastic boneresorption e.g. IL-1 (interleukin-1), TNF (tumor necrosis factor) andIL-6 (interleukin-6); while others primarily stimulate bone formatione.g. TGF-β (transforming growth factor-β), IGF (insulin-like growthfactor) and PDGF (platelet derived growth factor).

[0015] There is need for clinical and epidemiological research for theprevention and treatment of osteoporosis for gaining greater knowledgeof factors controlling bone cell activity and regulation of bone mineraland matrix formation and remodeling.

[0016] Bone develops via a number of processes. Mesenchymal cells candifferentiate directly into bone, as occurs in the flat bones of thecraniofacial skeleton; this process is termed intramembranousossification. Alternatively, cartilage provides a template for bonemorphogenesis, as occurs in the majority of human bones. The cartilagetemplate is replaced by bone in a process known as endochondralossification. Reddi (1981) Collagen Rel. Res. 1:209-226. Bone is alsocontinuously modeled during growth and development and remodeledthroughout the life of the organism in response to physical and chemicalsignals. Development and maintenance of cartilage and bone tissue duringembryogenesis and throughout the life-time of vertebrates is verycomplex. It is widely accepted that a multitude of factors, fromsystemic hormones to local regulatory factors such as the members of theTGF-p superfamily, cytokines and prostaglandins, act in concert toregulate the continuous processes of bone formation and bone resorption.Disturbance of the balance between osteoblastic bone deposition andosteoclastic bone resorption is responsible for many skeletal diseases.

[0017] Diseases of bone loss are a major public health problemespecially for women in all Western communities. The most common causeof osteopenia is osteoporosis; other causes include osteomalacia andbone disease related to hyperparathyroidism. Osteopenia has been definedas the appearance of decreased bone mineral content on radiography, butthe term more appropriately refers to a phase in the continuum fromdecreased bone mass to fractures and infirmity.

[0018] It is estimated that 30 million Americans are at risk forosteoporosis, the most common among these diseases, and there areprobably 100 million people similarly at risk worldwide. Melton (1995)Bone Min. Res. 10:175. These numbers are growing as the elderlypopulation increases. Despite recent successes with drugs that inhibitbone resorption, there is a clear need for specific anabolic agents thatwill considerably increase bone formation in people who have alreadysuffered substantial bone loss. There are no such drugs currentlyapproved.

[0019] Mechanical stimulation induces new bone formation in vivo andincreases osteoblastic differentiation and metabolic activity inculture. Mechanotransduction in bone tissue involves several steps: 1)mechanochemical transduction of the signal; 2) cell-to-cell signaling;and 3) increased number and activity of osteoblasts. Cell-to-cellsignaling after mechanical stimulus involves prostaglandins, especiallythose produced by COX-2, and nitric oxide. Prostaglandins induce newbone formation by promoting both proliferation and differentiation ofosteoprogenitor cells.

OBJECTS AND SUMMARY OF THE INVENTION

[0020] In a search for agents that enhance osteoblastproliferation/differentiation and bone formation, mechanical force wasemployed as an osteogenesis inducer and a proprietary gene discoverymethodology was carried out to detect genes that are specificallyexpressed in very early osteo-, chondro-progenitor cells.

[0021] The present invention provides human mechanical stress inducedgenes, expression products of such genes, uses for such genes andexpression products for treatment, prevention, control, of osteoporosisor factors or processes which are involved in bone diseases including,but not limited to, osteoporosis, osteopenia, osteopetrosis,osteosclerosis, osteoarthritis, periodontosis and bone fracture. Theinvention further provides diagnostic, treatment, prevention, controlmethods or processes as well as compositions.

[0022] The invention additionally provides an isolated nucleic acidmolecule, and the complement thereof, encoding the protein 608 or afunctional portion thereof or a polypeptide, which is at leastsubstantially homologous or identical thereto. The invention encompassesan isolated nucleic acid molecule encoding human protein 608 (or “OCP”)or a functional portion thereof.

[0023] The invention further encompasses a method for preventing,treating or controlling osteoporosis or low bone density or otherfactors associated with, causing or contributing to bone diseasesincluding, but not limited to, osteopenia, osteopetrosis,osteosclerosis, osteoarthritis, periodontosis or symptoms thereof, orother conditions involving mechanical stress or a lack thereof, byadministering to a subject in need thereof, a polypeptide or portionthereof provided herein; and accordingly, the invention comprehends usesof polypeptides in preparing a medicament or therapy for suchprevention, treatment or control.

[0024] The invention also comprehends a method for preventing, treatingor controlling osteoporosis or low bone density or other factors causingor contributing to osteoporosis or symptoms thereof or other conditionsinvolving mechanical stress or a lack thereof, by administering acomposition comprising a gene or functional portion thereof, an antibodyor portion thereof elicited by such an expression product or portionthereof; and, the invention thus further comprehends uses of such genes,expression products, antibodies, portions thereof, in the preparation ofa medicament or therapy for such control, prevention or treatment.

[0025] The invention further encompasses methods of use of Adlican asdescribed herein for any use of OCP. The Adlican gene, or functionalportions thereof, can likewise be used for any purpose described hereinfor an OCP gene. The invention further encompasses compositionscomprising a physiologically acceptable excipient and at least one ofAdlican, the Adlican gene and antibodies specific to Adlican.

[0026] These and other embodiments are disclosed or are obvious from andencompassed by, the Detailed Description which follows the BriefDescription of the Figures below.

BRIEF DESCRIPTION OF THE FIGURES

[0027] The following Detailed Description, given by way of example, butnot intended to limit the invention to specific embodiments described,may be understood in conjunction with the accompanying Figures, inwhich:

[0028]FIG. 1 shows the full rat 608 cDNA sequence (SEQ ID NO:1).

[0029]FIG. 2 shows the PcDNA3.1-608 construct.

[0030]FIG. 3 shows the OCP rat protein amino acid sequence (SEQ IDNO:2).

[0031]FIG. 4 shows the results of TNT (transcription—translation)assays.

[0032]FIG. 5 shows the structure of Bac 23-261L4.

[0033]FIG. 6 shows the structure of Bac 23-241H7.

[0034]FIG. 7 shows the sequence analysis of m608p-Lexicon clone (SEQ IDNO:3)—Partial re-sequence. (1) Re-sequenced regions are underlined; (2)Putative exons are in Bold lettering; and (3) ATG-First ATG of codingregion (in Italics).

[0035]FIG. 8 shows the mouse OCP exon and intron map.

[0036]FIG. 9 shows the OCP map of exon-intron borders.

[0037]FIG. 10 shows the sequence alignment between genomic human OCP(SEQ ID NO:4) and rat OCP cDNA (SEQ ID NO:5)-2 exons.

[0038]FIG. 11 shows the human OCP exon and intron list.

[0039]FIG. 12 shows the OCP human cDNA sequence (predicted codingregion, SEQ ID NO:6)

[0040]FIG. 13 shows the percent identity between A. rat protein/humanprotein; B. rat protein/mouse protein; C. rat cDNA/human cDNA; and D.rat cDNA/mouse cDNA.

[0041]FIG. 14 shows the alignment of rat, human, and mouse OCP cDNAcoding regions (rat cDNA: SEQ ID NO:7; human 5+3 corrected: SEQ ID NO:8;and mus cDNA 5: SEQ ID NO:9).

[0042]FIG. 15 shows the alignment of rat, human and mouse OCP proteins(rat: SEQ ID NO:10; human 5+3 corrected: SEQ ID NO:11; and mouse 5corrected: SEQ ID NO:12).

[0043]FIG. 16 shows the alignment of rat and human OCP proteins (rat:SEQ ID NO:13; and human 5+3 corrected: SEQ ID NO:14).

[0044]FIG. 17 shows the partial mouse OCP protein amino acid sequence(236 aa) (SEQ ID NO:15).

[0045]FIG. 18 shows the OCP human protein amino acid sequence (2587 aa)(SEQ ID NO:16).

[0046]FIG. 19 shows the OCP protein structure predicted from the OCPgene.

[0047]FIG. 20 shows a list of expression patterns of OCP in primarycells and various other cell lines. A. Northern blot of poly A+ RNART-PCR from rat primary calvaria cells and MC3T3 cells is shown. Themain 8.9kb transcript is present only in calvaria cells. RT-PCR assayswith specific OCP primers were performed on total RNA from various linesas indicated on the right side of the figure. In all assays similaramounts of GapDH RT-PCR products were detected in all RNA samples. Inaddition, B. no GapDH products were detected in any RNA samples, when RTwas omitted. (−) represents no expression of OCP, while (+) representsexpression. When (− +) are indicated, the expression of OCP is inducedonly upon specific conditions.

[0048]FIG. 21 shows the effects of mechanical stress on MC3T3pre-osteoblastic cells. RT-PCR for OCP, Cbfal, Osteopontin (OPN) andGAPDH transcripts are as indicated. The results shown are representativeof three experiments using total cellular RNA from MC3T3 cells that didnot undergo mechanical stress (1), and mechanically stimulated MC3T3cells (2). The RT-PCR products, were stained with ethidium bromide.

[0049]FIG. 22 shows OCP (608) expression in early stages of in vitroosteoblast differentiation from mesenchymal (C3H10T½) and pre-myoblast(C2C12) cells.

[0050]FIG. 23 shows that OCP is an early marker of endochondralossification in P7 rat femoral epiphysis.

[0051]FIG. 24 shows that OCP is induced during osteoblasticdifferentiation of bone marrow stroma cells and is a specific marker ofearly osteoblastic progenitors in bone marrow.

[0052]FIG. 25 shows in vivo regulation of OCP expression in bone marrowformation by various treatments. The results shown are representative ofthree experiments using total cellular RNA from treated two-month oldmice. The different treatments are indicated. The RT-PCR products aremarked. Control mice did not undergo any treatment. In each treatmentgroup the left lane represents negative control without the addition ofRT, the central lane represents the OCP RT-PCR product and the rightlane represents the GapDH RT-PCR product. Bone formation is shown byblood loss, estrogen administration; bon loss, by sciatic neurotomymodels.

[0053]FIG. 26 shows a low power microphotograph of fractured bone oneweek after the operation. Note that well-developed woven bone andfibrocartilagenous callus formed at the fracture site. Bone marrowtissue was mainly destroyed by insertion of the wire used for thefracture immobilization. Marked areas are presented at highermagnification in the following figures.

[0054]FIG. 27 shows microphotographs of the central part of callus, A.brightfield and B. darkfield. Cells expressing the OCP gene can be seenin the fibrous part of the callus. There was no hybridization signalfrom chondrocytes.

[0055]FIG. 28 shows microphotographs of the callus area marked by 2 inFIG. 26, A. brightfield and B. darkfield. Cells expressing the OCP genecan be seen in a highly vascularized subperiosteal area bordering thecartilagenous part of the callus.

[0056]FIG. 29 shows microphotographs of the highly vascularizedendiosteal tissue. This was developed in reaction to the wire insertion(area 3 on FIG. 26), A. brightfield and B. darkfield. This tissuecontains many cells expressing the OCP gene.

[0057]FIG. 30 shows a high power microphotograph of perivascular cells.The perivascular cells express the 608 gene within lacuna of woven bonearrowheads.

[0058]FIG. 31 shows a high power microphotograph of periosteum coveringthe woven bone. Multiple cells display expression of the 608 gene inperiosteum. Arrowheads point to two 608 expressing cells within thewoven bone.

[0059]FIG. 32 shows A. brightfield and B. darkfield microphotographs ofa section of fractured bone healed for 4 weeks. Multiple cells inperiosteal tissue area of active remodeling of the cancellous bonecovering the callus show a hybridization signal.

[0060]FIG. 33 shows the boxed area of FIG. 32 presented at highermagnification. Several OCP-expressing cells are concentrated in vasculartissue that fills the cavities resulting from osteoclast activity(marked by astrisks).

[0061]FIG. 34 shows in vitro induction of osteoblastic differentiationby transfected OCP.

[0062]FIG. 35 shows transient transfections of OCP deletion constructsto calvaria cells. Two OCP deletion constructs (OCP-403,OCP-760) and OCPfull length construct were transiently transfected to primary calvariacells. ALP staining is presented. All deletion constructs show increasedosteoblastic colony numbers and colony size compared with transienttransfection of the control pCDNA vector.

[0063]FIG. 36 shows increased osteoblast differentiation inOCP-transfected ROS cells. RT-PCR assays were with OCP, Cbfal, ALP, BSPand GapDH specific primers as indicated above. The results shown arerepresentative of two experiments using total cellular RNA from: (1) thestable OCP-expressed ROS cell line; and (2) the control ROS cell line(stable transfection with pCDNA). The OCP RT-PCR product is 1020 bp, theCbfal product is 289 bp, the ALP product is 226 bp, the BSP product is1048 bp and the GapDH (control) product is 450 bp long. M representsprotein markers.

[0064]FIG. 37 shows increased osteoblast proliferation inOCP-transfected ROS cells.

[0065]FIG. 38 shows OCP induction of bone formation ex vivo. Biggerbones and higher bone mass density were found in bones co-cultivatedwith OCP transfected cells.

[0066]FIG. 39 shows the structure of the Osteocalcin promoter—OCP gene.

[0067]FIG. 40 shows autoradiograms of Southern blot analysis of placentaDNAs. “A” shows the results of a Southern blot on the DNA samples fromall developed embryos. (Sample 10 is missing due to lack of embryo inthe sample). “F,” the injected fragment, served as positive control forthe expected size, the arrow marks the expected fragment. “B” shows asection of the autoradiogram of “A” exposed to the sample for additionaltime. These autoradiograms show that both embryos 20 and 21 aretransgenic. “C” shows a repetition of the Southern blot on DNA fromthree selected embryos, 11, 20 and 21. Embryos 20 and 21 are againdetected as transgenic. Embryo 11, which gave an obscured signal on thelonger exposure of “A”, is also detected as transgenic in “C.” “F” isgenomic DNA from a stable transgenic line produced later. The correctfragment is indicated by an arrow. The more intense fragment found belowis a non-specific fragment occasionally observed with the SV40 probe.

[0068]FIG. 41 shows A. exogenic OCP expression in transgenic embryos.RT-PCR for exogenic OCP transcripts was performed. The results arerepresentative of three experiments using total cellular RNA from embryotails. The RT-PCR products that are marked were visualized by stainingwith ethidium bromide. B. GapDH primers were used to show thatdifferences in OCP transcript abundance did not reflect variation in theefficiency of the RT reaction.

[0069]FIG. 42 shows the characterization of osteocalcin promoter of OCPtransgenic embryos (E17 embryos). Calvaria, tibia and femur lengths weremeasured in μm. All measurements include only the calcified regionsstained by Alizarin Red. A. shows calvaria length/width, B. showscalvaria length/width (%).

[0070]FIG. 43 shows Alizarin Red staining of OC-OCP transgenic embryolong bones showing that OCP induces bone formation in vivo. Cells shownare osteoblasts, chondrocytes and liver/bloodstream.

[0071]FIG. 44 shows Alizarin Red staining of calvaria bones fromtransgenic and control embryos. Higher calcification (represented byAlizarin Red staining) was detected when transgenic embryo calvariabones were stained in comparison with their littermates. The transgenicembryo calvaria bones were longer and wider.

[0072]FIG. 45 compares clone 14C10 to the Lexicon clone.

[0073]FIG. 46 shows pMCSIEm608prm5.5.

[0074]FIG. 47 shows the sequence of the mouse OCP promoter region(proximal 5.5 kb fragment) (SEQ ID NO:17) cloned into pMCSIE/pGL3-basic.

[0075]FIG. 48 shows the sequence of the 5′ end of clone p14C10 (SEQ IDNO:18) encoding the mouse OCP promoter region.

[0076]FIG. 49 shows the proximal regulatory region of human and mouseOCP genes.

[0077]FIG. 50 shows the sequences of the primer (SEQ ID NO:19) and QB3(CMF608) (SEQ ID NO:20).

[0078]FIG. 51 shows the Adlican and amino acid sequence (SEQ ID NO: 21).

[0079]FIG. 52 shows the Adlican mRNA sequence (SEQ ID NO: 22)

DETAILED DESCRIPTION OF THE INVENTION

[0080] The present invention is related to the discovery of a novelgene, CMF608 (“OCP”), the expression of which is upregulated bymechanical stress on primary calvaria cells. Several functional featuresidentify OCP as the most specific early marker of osteo- orchondro-progenitor cells as well as an inducer of osteoblastproliferation and differentiation As used herein, the same gene of theinvention may be referred to either as “608” or “OCP.” RNA refers to RNAisolated from cell cultures, cultured tissues or cells or tissuesisolated from organisms which are stimulated, differentiated, exposed toa chemical compound, infected with a pathogen, or otherwise stimulated.As used herein, translation is defined as the synthesis of proteinencoded by an mRNA template.

[0081] As used herein, stimulation of translation, transcription,stability or transportation of unknown target mRNA or stimulatingelement, includes chemically, pathogenically, physically, or otherwiseinducing or repressing an mRNA population encoded by genes derived fromnative tissues and/or cells under pathological and/or stress conditions.In other words, stimulating the expression of an mRNA with a stressinducing element or “stressor” includes, but is not limited to, theapplication of an external cue, stimulus, or stimuli that stimulates orinitiates translation of an mRNA stored as untranslated mRNA in thecells from the sample. The stressor may cause an increase in stabilityof certain mRNAs, or induce the transport of specific mRNAs from thenucleus to the cytoplasm. The stressor may also induce specific genetranscription. In addition to stimulating translation of mRNA from genesin native cells/tissues, stimulation can include induction and/orrepression of genes under pathological and/or stress conditions. Themethod utilizes a stimulus or stressor to identify unknown target genesregulated at the various possible levels by the stress inducing elementor stressor.

[0082] More in particular, with respect to nucleic acid molecules (rat608 and human 608 genes) and polypeptides expressed from them, theinvention further comprehends isolated and/or purified nucleic acidmolecules and isolated and/or purified polypeptides having at leastabout 70%, preferably at least about 75% or about 77% identity orhomology (“substantially homologous or identical”); advantageously atleast about 80% or about 83%, such as at least about 85% or about 87%homology or identity (“significantly homologous or identical”); forinstance at least about 90% or about 93% identity or homology (“highlyhomologous or identical”); more advantageously at least about 95%, e.g.,at least about 97%, about 98%, about 99% or even about 100% identity orhomology (“very highly homologous or identical” to “identical”); or fromabout 84-100% identity considered (“highly conserved”). The inventionalso comprehends that these nucleic acid molecules and polypeptides canbe used in the same fashion as the herein or aforementioned nucleic acidmolecules and polypeptides.

[0083] Nucleotide sequence homology can be determined using the “Align”program of Myers and Miller, ((1988) CABIOS 4:11-17) and available atNCBI. Alternatively or additionally, the term “homology” or “identity,”for instance, with respect to a nucleotide or amino acid sequence, canindicate a quantitative measure of homology between two sequences. Thepercent sequence homology can be calculated as(N_(ref)−N_(dif))*100/N_(ref), wherein N_(dif) is the total number ofnon-identical residues in the two sequences when aligned and whereinN_(ref) is the number of residues in one of the sequences. Hence,AGTCAGTC has a sequence similarity of 75% to AATCAATC (N_(ref)=8;N_(dif)=2).

[0084] Alternatively or additionally, “homology” or “identity” withrespect to sequences can refer to the number of positions with identicalnucleotides or amino acid residues divided by the number of nucleotidesor amino acid residues in the shorter of the two sequences whereinalignment of the two sequences can be determined in accordance with theWilbur and Lipman algorithm ((1983) Proc. Natl. Acad. Sci. USA 80:726),for instance, using a window size of 20 nucleotides, a word length of 4nucleotides, and a gap penalty of 4, and computer-assisted analysis andinterpretation of the sequence data including alignment can beconveniently performed using commercially available programs (e.g.,Intelligenetics™ Suite, Intelligenetics Inc., CA). When RNA sequencesare said to be similar, or have a degree of sequence identity orhomology with DNA sequences, thymidine (T) in the DNA sequence isconsidered equal to uracil (U) in the RNA sequence (see also alignmentused in the Figures). RNA sequences within the scope of the inventioncan be derived from DNA sequences or their complements, by substitutingthymidine (T) in the DNA sequence with uracil (U).

[0085] Additionally or alternatively, amino acid sequence similarity oridentity or homology can be determined, for instance, using the BlastPprogram (Altschul et al. Nucl. Acids Res. 25:3389-3402) and available atNCBI. The following references provide algorithms for comparing therelative identity or homology of amino acid residues of two proteins,and additionally, or alternatively, with respect to the foregoing, theteachings in these references can be used for determining percenthomology or identity. Smith et al. (1981) Adv. Appl. Math. 2:482-489;Smith et al. (1983) Nucl. Acids Res. 11:2205-2220; Devereux et al.(1984) Nucl. Acids Res. 12:387-395; Feng et al. (1987) J. Molec. Evol.25:351-360; Higgins et al. (1989) CABIOS 5:151-153; and Thompson et al.(1994) Nucl. Acids Res. 22:4673480.

[0086] As to uses, the inventive genes and expression products as wellas genes identified by the herein disclosed methods and expressionproducts thereof and the compositions comprising Adlican or the Adlicangene (including “functional” variations of such expression products, andtruncated portions of herein defined genes such as portions of hereindefined genes which encode a functional portion of an expressionproduct) are useful in treating, preventing or controlling or diagnosingmechanical stress conditions or absence or reduced mechanical stressconditions.

[0087] As described herein, Adlican, including functional portionsthereof, can be used in all methods suitable for OCP. The sequencehomology between Adlican and human OCP provides this novel use of theAdlican protein. Adlican is provided, for instance, inAF245505.1:1.8487. Adlican is named for “ADhesion protein withLeucine-rich repeats has immunoglobulin domains related to perleCAN”;and shows elevated expression in cartilage from osteoarthritis patients.The Adlican gene, or functional portions thereof, can likewise be usedfor any purpose described herein for an OCP gene. The invention furtherencompasses compositions comprising a physiologically acceptableexcipient and at least one of Adlican, the Adlican gene and antibodiesspecific to Adlican.

[0088] For instance, OCP expression is related to proliferation anddifferentation of osteoblasts and chondrocytes. The expression productof OCP, or cells or vectors expressing OCP may cause cells toselectively proliferate and differentiate and thereby increase or alterbone density. Detecting levels of OCP mRNA or expression and comparingit to “normal” non-osteopathic levels may allow one to detect subjectsat risk for osteoporosis or lower levels of osteoblasts andchondrocytes.

[0089] The medicament or treatment can be any conventional medicament ortreatment for osteoporosis. Alternatively, or additionally, themedicament or treatment can be the particular protein of the genedetected in the inventive methods, or that which inhibits that protein,e.g., binds to it. Similarly, additionally, or alternatively, themedicament or treatment can be a vector which expresses the protein ofthe gene detected in the inventive methods or that which inhibitsexpression of that gene; again, for instance, that which can bind to itand/or otherwise prevents its transcription or translation. Theselection of administering a protein or that which expresses it, or ofadministering that which inhibits the protein or the gene expression,can be done without undue experimentation, e.g., based ondown-regulation or up-regulation as determined by inventive methods(e.g., in the osteoporosis model).

[0090] In the practice of the invention, one can employ general methodsin molecular biology. Standard molecular biology techniques known in theart and not specifically described are generally followed as in Sambrooket al. (1989, 1992) Molecular Cloning: A Laboratory Manual, Cold SpringHarbor Laboratory, New York; and Ausubel et al. (1989) Current Protocolsin Molecular Biology, John Wiley and Sons, Baltimore, Md.

[0091] PCR comprising the methods of the invention is performed in areaction mixture comprising an amount, typically between <10 ng-200 ngtemplate nucleic acid; 50-100 p moles each oligonucleotide primer;1-1.25 mM each deoxynucleotide triphosphate; a buffer solutionappropriate for the polymerase used to catalyze the amplificationreaction; and 0.5-2 Units of a polymerase, most preferably athermostable polymerase (e.g., Taq polymerase or Tth polymerase).

[0092] Antibodies may be used in various aspects of the invention, e.g.,in detection or treatment or prevention methods. Antibodies can bemonoclonal, polyclonal or recombinant for use in the immunoassays orother methods of analysis necessary for the practice of the invention.Conveniently, the antibodies may be prepared against the immunogen orantigenic portion thereof for example a synthetic peptide based on thesequence, or prepared recombinantly by cloning techniques or the naturalgene product and/or portions thereof may be isolated and used as theimmunogen. The genes are identified as set forth in the presentinvention and the gene product identified. Immunogens can be used toproduce antibodies by standard antibody production technology well knownto those skilled in the art as described generally in Harlow and Lane(1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory,Cold Spring Harbor, N.Y.; and Borrebaeck (1992) Antibody Engineering—APractical Guide, W.H. Freeman and Co. Antibody fragments can also beprepared from the antibodies and include Fab, F(ab′)2, Fv and scFvprepared by methods known to those skilled in the art. Bird et al.(1988) Science 242:423-426. Any peptide having sufficient flexibilityand length can be used as an scFv linker. Usually the linker is selectedto have little to no immunogenicity. An example of a linking peptide is(GGGGS)₃, which bridges approximately 3.5 nm between the C-terminus ofone V region and the N-terminus of another V region. Other linkersequences can also be used, and can provide additional functions, suchas a means for attaching a drug or a solid support.

[0093] For producing polyclonal antibodies, a host, such as a rabbit orgoat, is immunized with the immunogen or an immunogenic fragmentthereof, generally with an adjuvant and, if necessary, coupled to acarrier; and antibodies to the immunogen are collected from the sera ofthe immunized animal. The sera can be adsorbed against relatedimmunogens so that no cross-reactive antibodies remain in the serarendering the polyclonal antibody monospecific.

[0094] For producing monoclonal antibodies (mAbs), an appropriate donor,generally a mouse, is hyperimmunized with the immunogen and splenicantibody producing cells are isolated. These cells are fused to animmortal cell, such as a myeloma cell, to provide an immortal fused cellhybrid that secretes the antibody. The cells are then cultured, in bulk,and the mAbs are harvested from the culture media for use. Hybridomacell lines provide a constant, inexpensive source of chemicallyidentical antibodies and preparations of such antibodies can be easilystandardized. Methods for producing mAbs are well known to those ofordinary skill in the art. See, e.g. U.S. Pat. No. 4,196,265.

[0095] For producing recombinant antibodies, mRNAs from antibodyproducing B lymphocytes of animals, or hybridomas arereverse-transcribed to obtain cDNAs. See generally, Huston et al. (1991)Met. Enzymol. 203:46-88; Johnson and Bird (1991) Met. Enzymol.203:88-99; and Mernaugh and Mernaugh (1995) In, Molecular Methods inPlant Pathology (Singh and Singh eds.) CRC Press Inc. Boca Raton, Fla.,pp. 359-365). Antibody cDNA, which can be full or partial length, isamplified and cloned into a phage or a plasmid. The cDNA can be apartial length of heavy and light chain cDNA, separated or connected bya linker. The antibody, or antibody fragment, is expressed using asuitable expression system to obtain recombinant antibody. Antibody cDNAcan also be obtained by screening pertinent expression libraries.

[0096] Antibodies can be bound to a solid support substrate orconjugated with a detectable moiety or be both bound and conjugated asis well known in the art. For a general discussion of conjugation offluorescent or enzymatic moieties see, Johnston and Thorpe (1982)Immunochemistry in Practice, Blackwell Scientific Publications, Oxford.The binding of antibodies to a solid support substrate is also wellknown in the art. See for a general discussion, Harlow and Lane (1988);and Borrebaeck (1992). The detectable moieties contemplated with thepresent invention include, but are not limited to, fluorescent,metallic, enzymatic and radioactive markers such as biotin, gold,ferritin, alkaline phosphatase, β-galactosidase, peroxidase, urease,fluorescein, rhodamine, tritium, ¹³C and iodination.

[0097] Antibodies can also be used as an active agent in a therapeuticcomposition and such antibodies can be humanized, for instance, toenhance their effects. See, Huls et al. Nature Biotech. 17:1999.“Humanized” antibodies are antibodies in which at least part of thesequence has been altered from its initial form to render it more likehuman immunoglobulins. In one version, the H chain and L chain C regionsare replaced with human sequence. In another version, the CDR regionscomprise amino acid sequences from the antibody of interest, while the Vframework regions have also been converted human sequences. See, forexample, EP 0329400. In a third version, V regions are humanized bydesigning consensus sequences of human and mouse V regions, andconverting residues outside the CDRs that are different between theconsensus sequences. The invention encompasses humanized mAbs.

[0098] The expression product from the gene or portions thereof can beuseful for generating antibodies such as monoclonal or polyclonalantibodies which are useful for diagnostic purposes or to block activityof expression products or portions thereof or of genes or a portionthereof, e.g., as therapeutics.

[0099] The genes of the present invention or portions thereof, e.g., aportion thereof which expresses a protein which function the same as oranalogously to the full length protein, or genes identified by themethods herein can be expressed recombinantly, e.g., in Escherichia colior in another vector or plasmid for either in vivo expression or invitro expression. The methods for making and/or administering a vectoror recombinant or plasmid for expression of gene products of genes ofthe invention or identified by the invention or a portion thereof eitherin vivo or in vitro can be any desired method, e.g., a method which isby or analogous to the methods disclosed in: U.S. Pat. Nos. 4,603,112;4,769,330; 5,174,993; 5,505,941; 5,338,683; 5,494,807; 4,394,448;4,722,848; 4,745,051; 4,769,331; 5,591,639; 5,589,466; 4,945,050;5,677,178; 5,591,439; 5,552,143; and 5,580,859; U.S. patent applicationSer. No. 920,197, filed Oct. 16, 1986; WO 94/16716; WO 96/39491;WO91/11525; WO 98/33510; WO 90/01543; EP 0 370 573; EP 265785; Paoletti(1996) Proc. Natl. Acad. Sci. USA 93:11349-11353; Moss (1996) Proc.Natl. Acad. Sci. USA 93:11341-11348; Richardson (Ed) (1995) Methods inMolecular Biology 39, “Baculovirus Expression Protocols,” Humana PressInc.; Smith et al. (1983) Mol. Cell. Biol. 3:2156-2165; Pennock et al.(1984) Mol. Cell. Biol. 4:399-406; Roizman Proc. Natl. Acad. Sci. USA93:11307-11312; Andreansky et al. Proc. Natl. Acad. Sci. USA93:11313-11318; Robertson et al. Proc. Natl. Acad. Sci. USA93:11334-11340; Frolov et al. Proc. Natl. Acad. Sci. USA 93:11371-11377;Kitson et al. (1991) J. Virol. 65:3068-3075; Grunhaus et al. (1992) Sem.Virol. 3:237-52; Ballay et al. (1993) EMBO J. 4:3861-65; Graham (1990)Tibtech 8:85-87; Prevec et al. J. Gen. Virol. 70:429-434; Felgner et al.(1994) J. Biol. Chem. 269:2550-2561; (1993) Science 259:1745-49;McClements et al. (1996) Proc. Natl. Acad. Sci. USA 93:11414-11420; Juet al. (1998) Diabetologia 41:736-739; and Robinson et al. (1997) Sem.Immunol. 9:271-283.

[0100] The expression product generated by vectors or recombinants canalso be isolated and/or purified from infected or transfected cells; forinstance, to prepare compositions for administration to patients.However, in certain instances, it may be advantageous to not isolateand/or purify an expression product from a cell; for instance, when thecell or portions thereof enhance the effect of the polypeptide.

[0101] As used herein, “treatment” refers to clinical intervention in anattempt to alter the natural course of the individual or cell beingtreated, and may be performed either for prophylaxis or during thecourse of clinical pathology. Desirable effects of the treatment includepreventing occurrence or recurrence of disease, alleviation of symptoms,diminishment of any direct or indirect pathological consequences of thedisease, preventing metastases, decreasing the rate of diseaseprogression, amelioration or palliation of the disease state, andremission or improved prognosis.

[0102] An inventive vector or recombinant expressing a gene or a portionthereof identified herein or from a method herein can be administered inany suitable amount to achieve expression at a suitable dosage level,e.g., a dosage level analogous to the herein mentioned dosage levels(wherein the gene product is directly present). The inventive vector orrecombinant nucleotide can be administered to a patient or infected ortransfected into cells in an amount of about at least 10³ pfu; morepreferably about 10⁴ pfu to about 10¹⁰ pfu, e.g., about 10⁵ pfu to about10⁹ pfu, for instance about 10⁶ pfu to about 10⁸ pfu. In plasmidcompositions, the dosage should be a sufficient amount of plasmid toelicit a response analogous to compositions wherein gene product or aportion thereof is directly present; or to have expression analogous todosages in such compositions; or to have expression analogous toexpression obtained in vivo by recombinant compositions. For instance,suitable quantities of plasmid DNA in plasmid compositions can be 1 μgto 100 mg, preferably 0.1 to 10 mg, e.g., 500 μg, but lower levels suchas 0.1 to 2 mg or preferably 1-10 μg may be employed. Documents citedherein regarding DNA plasmid vectors can be consulted for the skilledartisan to ascertain other suitable dosages for DNA plasmid vectorcompositions of the invention, without undue experimentation.

[0103] Compositions for administering vectors can be as in or analogousto such compositions in documents cited herein or as in or analogous tocompositions herein described, e.g., pharmaceutical or therapeuticcompositions and the like.

[0104] Thus, the invention comprehends in vivo gene expression which issometimes termed “gene therapy.” Gene therapy can refer to the transferof genetic material (e.g. DNA or RNA) of interest into a host subject orpatient to treat or prevent a genetic or acquired disease, condition orphenotype. The particular gene that is to be used or which has beenidentified as the target gene is identified as set forth herein. Thegenetic material of interest encodes a product (e.g. a protein,polypeptide, peptide or functional RNA) the production in vivo of whichis desired. For example, the genetic material of interest can encode ahormone, receptor, enzyme, polypeptide or peptide of therapeutic value.For a review see, in general, the text “Gene Therapy” (Advances inPharmacology 40, Academic Press, 1997).

[0105] Two basic approaches to gene therapy have evolved: (1) ex vivo;and (2) in vivo gene therapy. In ex vivo gene therapy cells are removedfrom a patient, and while being cultured are treated in vitro.Generally, a functional replacement gene is introduced into the cell viaan appropriate gene delivery vehicle/method (transfection, homologousrecombination, etc.) and, an expression system as needed and then themodified cells are expanded in culture and returned to the host/patient.These genetically reimplanted cells have been shown to produce thetransfected gene product in situ. In in vivo gene therapy, target cellsare not removed from the subject; rather, the gene to be transferred isintroduced into the cells of the recipient organism in situ, that iswithin the recipient. Alternatively, if the host gene is defective, thegene is repaired in situ. Culver (1998) Antisense DNA & RNA BasedTherapeutics, February, 1998, Coronado, Calif. These genetically alteredcells have been shown to produce the transfected gene product in situ.

[0106] The gene expression vehicle is capable of delivery/transfer ofheterologous nucleic acid into a host cell. The expression vehicle mayinclude elements to control targeting, expression and transcription ofthe nucleic acid in a cell-selective manner as is known in the art. Itshould be noted that often the 5′UTR and/or 3′UTR of the gene may bereplaced by the 5′ UTR and/or 3′UTR of the expression vehicle.Therefore, as used herein, the expression vehicle may, as needed, notinclude the 5′UTR and/or 3′UTR shown in sequences herein and onlyinclude the specific amino acid coding region.

[0107] The expression vehicle can include a promoter for controllingtranscription of the heterologous material and can be either aconstitutive or inducible promoter to allow selective transcription.Enhancers that may be required to obtain necessary transcription levelscan optionally be included. Enhancers are generally any non-translatedDNA sequence that works contiguously with the coding sequence (in cis)to change the basal transcription level dictated by the promoter. Theexpression vehicle can also include a selection gene as describedherein.

[0108] Vectors can be introduced into cells or tissues by any one of avariety of known methods within the art. Such methods can be foundgenerally described in Sambrook et al. (1989, 1992); Ausubel et al.(1989); Chang et al. (1995) Somatic Gene Therapy, CRC Press, Ann Arbor,Mich.; Vega et al. (1995) Gene Targeting, CRC Press, Ann Arbor, Mich.;Vectors: A Survey of Molecular Cloning Vectors and Their Uses,Butterworths, Boston Mass. (1988); and Gilboa et al. (1986) BioTech.4:504-512, as well as other documents cited herein and include, forexample, stable or transient transfection, lipofection, electroporationand infection with recombinant viral vectors. In addition, see U.S. Pat.No. 4,866,042 for vectors involving the central nervous system; and alsoU.S. Pat. Nos. 5,464,764 and 5,487,992 for positive-negative selectionmethods.

[0109] Introduction of nucleic acids by infection offers advantages overthe other listed methods. Higher efficiency can be obtained due to theirinfectious nature. Moreover, viruses are very specialized and typicallyinfect and propagate in specific cell types. Thus, their naturalspecificity can be used to target the vectors to specific cell types invivo or within a tissue or mixed cell culture. Viral vectors can also bemodified with specific receptors or ligands to alter target specificitythrough receptor-mediated events.

[0110] Additional features can be added to the vector to ensure itssafety and/or enhance its therapeutic efficacy. Such features include,for example, markers that can be used to negatively select against cellsinfected with the recombinant virus. An example of such a negativeselection marker is the TK gene described above that confers sensitivityto the antibiotic gancyclovir. Negative selection is therefore a meansby which infection can be controlled because it provides induciblesuicide through the addition of antibiotic. Such protection ensures thatif, for example, mutations arise that produce altered forms of the viralvector or recombinant sequence, cellular transformation will not occur.Features that limit expression to particular cell types can also beincluded. Such features include, for example, promoter and regulatoryelements that are specific for the desired cell type.

[0111] In addition, recombinant viral vectors are useful for in vivoexpression of a desired nucleic acid because they offer advantages suchas lateral infection and targeting specificity. Lateral infection isinherent in the life cycle of, for example, retrovirus and is theprocess by which a single infected cell produces many progeny virionsthat bud off and infect neighboring cells. The result is that a largearea becomes rapidly infected, most of which was not initially infectedby the original viral particles. This is in contrast to vertical-type ofinfection in which the infectious agent spreads only through daughterprogeny. Viral vectors can also be produced that are unable to spreadlaterally. This characteristic can be useful if the desired purpose isto introduce a specified gene into only a localized number of targetedcells.

[0112] Delivery of gene products (products from herein defined genes:genes identified herein or by inventive methods or portions thereof)and/or antibodies or portions thereof and/or agonists or antagonists(collectively or individually “therapeutics”), and compositionscomprising the same, as well as of compositions comprising a vectorexpressing gene products, can be done without undue experimentation fromthis disclosure and the knowledge in the art.

[0113] The pharmaceutically “effective amount” for purposes herein isthus determined by such considerations as are known in the art. Theamount must be effective to achieve improvement including but notlimited to improved survival rate or more rapid recovery, or improvementor amelioration or elimination of symptoms and other indicators, e.g.,of osteoporosis, for instance, improvement in bone density, as areselected as appropriate measures by those skilled in the art.

[0114] It is noted that humans are treated generally longer than themice or other experimental animals exemplified herein. Human treatmenthas a length proportional to the length of the disease process and drugeffectiveness. The doses may be single doses or multiple doses over aperiod of several days, but single doses are preferred. Thus, one canscale up from animal experiments, e.g., rats, mice, and the like, tohumans, by techniques from this disclosure and the knowledge in the art,without undue experimentation.

[0115] The present invention provides an isolated nucleic acid moleculecontaining nucleotides having a sequence set forth in at least one ofSEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:6 or SEQ ID NO:20, supplementsthereof and a polynucleotide having a sequence that differs from SEQ IDNO:1, SEQ ID NO:3, SEQ ID NO:6 or SEQ ID NO:20 due to the degeneracy ofthe genetic code or a functional portion thereof or a polynucleotidewhich is at least substantially homologous or identical thereto. In aprefered embodiment, the nucleic acid molecule comprises apolynucleotide having at least 15 nucleotides from SEQ ID NO: 1, SEQ IDNO:3, SEQ ID NO:6 or SEQ ID NO:20, prefereably at least 50 nucleotidesand more preferably at least 100 nucleotides.

[0116] The present invention also provides a composition of the isolatednucleic acid molecule, a vector comprising the isolated nucleic acidmolecule, a composition containing said vector and a method forpreventing, treating or controlling bone diseases including, but notlimited to, osteoporosis, osteopenia, osteopetrosis, osteosclerosis,osteoarthritis, periodontosis, bone fractures or low bone density or orother conditions involving mechanical stress or a lack thereof in asubject, comprising administering the inventive composition, or theinventive vector, and a method for preparing a polypeptide comprisingexpressing the isolated nucleic acid molecule or comprising expressingthe polypeptide from the vector.

[0117] The present invention further provides a method for preventing,treating or controlling osteoporosis, osteopenia, osteopetrosis,osteosclerosis, osteoarthritis, periodontosis, bone fractures or lowbone density or other factors causing or contributing to osteoporosis orsymptoms thereof or other conditions involving mechanical stress or alack thereof in a subject, comprising administering an isolated nucleicacid molecule or functional portion thereof or a polypeptide comprisingan expression product of the gene or functional portion of thepolypeptide or an antibody to the polypeptide or a functional portion ofthe antibody. In one embodiment of the invention, the isolated nucleicacid molecule encodes a 10 kD to 30 kD N-terminal cleavage product ofthe OCP protein. Preferably, the N-terminal cleavage product comprisesof a polypeptide of about 25 kD.

[0118] The present invention provides an isolated polypeptide encoded bythe inventive polynucleotide. In one embodiment of the invention, thepolypeptide is identified as human OCP or a functional portion thereofor a polypeptide which is at least substantially homologous or identicalthereto. Preferably, the functional portion comprises a N-terminalpolypeptide having a molecular weight of 10 kD to 30 kD. Morepreferably, the the functional portion comprises an N-terminalpolypeptide having a molecular weight of about 25 kD.

[0119] The present invention also provides a composition comprising oneor of isolated polypeptides, an antibody specific for the polypeptide ora functional portion thereof, a composition comprising the antibody or afunctional portion thereof, and a method for treating or preventingosteoporosis, or fracture healing, bone elongation, or periodontosis ina subject, comprising administering to the subject a N-terminalpolypeptide having a molecular weight of between 10 kD and 30 kD,preferably about 25 kD.

[0120] The present invention provides for a method of treating orpreventing osteoarthritis, osteopetrosis, or osteosclerosis, comprisingadministering to a subject an effective amount of a chemical or aneutralizing mAbs that inhibit the activity of the N-terminalpolypeptide having a molecular weight of between 10 kD and 30 kD,preferably about 25 kD.

[0121] As used herein, the term “subject,” “patient,” “host” include,but are not limited to human, bovine, pig, mouse, rat, goat, sheep andhorse.

[0122] Those skilled in the art will recognize that the components ofthe compositions should be selected to be chemically inert with respectto the gene product and optional adjuvant or additive. This will presentno problem to those skilled in chemical and pharmaceutical principles,or problems can be readily avoided by reference to standard texts or bysimple experiments (not involving undue experimentation), from thisdisclosure and the documents cited herein.

[0123] A better understanding of the present invention and of its manyadvantages will be had from the following examples, given by way ofillustration and as a further description of the invention.

Experimental Details

[0124] TGF-β1 is known as a principal inducer of connective tissuegrowth factor (CTGF, cef10, fisp12, cyr61, βIG-M1, βIG-M2,non-protooncogene) expression. The latter contains four distinctstructural modules, each of them homologous to distinct domains in otherextracellular proteins such as von Willebrand factor, slit,thrombospondins, fibrillar collagens, IGF-binding proteins and mucins.CTGF expression is induced not only by TGF-β1, but also by BMP2 (bonemorphogenic factor 2) and during wound repair. In embryogenesis, itsexpression is found in developing cartilaginous elements, includinglimbs, ribs, prevertebrae, chondrocranium and craniofascial elements(Meckel's cartilage). Thus, CTGF transcription correlates withdifferentiation of chondrocytes of both mesodermal and ectodermalorigin. In culture, CTGF is expressed in chondrocytes but not inosteoblasts. A possible role for CTGF in endochondral ossification issuspected because of its responsiveness to BMP2. In fibroblasts, CTGFexpression causes upregulation of α-1-collagen, α-5-integrin andfibronectin.

EXAMPLE 1 CMF608 Gene Expression by in Situ Hybridization

[0125] The CMF608 gene expression pattern was studied by in situhybridization on sections of bones from ovariectomized and sham-operatedrats. Female Wistar rats weighing 300-350 g were subjected toovariectomy under general anesthesia. Control rats were operated on inthe same way but ovaries were not excised—sham operation.

[0126] Three weeks after the operation, rats were sacrificed and tibiawere excised together with the knee joint. Bones were fixed for threedays in 4% paraformaldehyde and then decalcified for four days in asolution containing 5% formic acid and 10% fermalin. Decalcified boneswere postfixed in 10% formalin for three days and embedded intoparaffin.

[0127] The ectopic bone formation model was employed to study the bonedevelopment CMF608 gene expression pattern. Rat bone marrow cells wereseeded into cylinders of demineralized bone matrix prepared from rattibiae. Cylinders were implanted subcutaneously into adult rats. Afterthree weeks, rats were sacrificed and implants were decalcified andembedded into paraffin as described above for tibial bones.

[0128] The 6 μm sections were prepared and hybridized in situ. Afterhybridization, sections were dipped into nuclear track emulsion andexposed for three weeks at 4° C. Autoradiographs were developed, stainedwith hematoxylin-eosin and studied under microscopy using brightfieldand darkfield illumination.

[0129] For further assessment of cell and tissue specificity of CMF608gene expression, an in situ hybridization study was performed onsections of multitissue block containing multiple samples of adult rattissues. The CMF608 expression developmental pattern was studied onsagittal sections of mouse embryos of 12.5, 14.5 and 16.5 dayspostconception (dpc) stages.

[0130] Microscopic study of hybridized sections of long bones revealed apeculiar pattern of CMF608 probe hybridization. The hybridization signalcan be seen mainly in fibroblast-like cells found in several locationsthroughout the sections. Prominent accumulations of these cells can beseen in the area of periosteal modeling in metaphysis, and also inregions of active remodeling of compact bone in diaphysis: at theboundary between bone marrow and endosteal osteoblasts and inperiosteum; also in close contact with osteoblasts. Perivascularconnective tissue filling Volkmann's canals in compact bone in diaphysisand epiphysis also contains CMF608-expressing cells. No hybridizationwas found within cancellous bone and in bone marrow. This hybridizationpattern suggests that cells expressing CMF608 are associated with areasof remodeling of preexisting bone and are not involved in primaryendochondral ossification.

[0131] At the growth plate level, CMF608 expressing cells can be seen inthe perichondral fibrous ring of LaCroix. Some investigators regard thisfibrous tissue as the aggregation of residual mesenchymal cells able todifferentiate into both osteoblasts and chondrocytes. In this respect itis noteworthy that single cells expressing CMF608 can be seen inepiphyseal cartilage. These CMF608-expressing cells are rounded cellswithin the lateral segment of epiphysis (sometimes in close vicinity tothe LaCroix ring) and flattened cells covering the articulate surface.Most cells in articulate cartilage and all chondrocytes on the growthplate do not show CMF608 expression. Ovariectomy did not alter theintensity and pattern of CMF608 expression in bone tissue.

[0132] In ectopic bone sections, CMF608 hybridization signal can be seenin some fibroblast-like cells either scattered within unmineralizedconnective tissue matrix or concentrated at the boundary between thistissue and osteoblasts of immature bone.

[0133] CMF608 gene expression patterns revealed by in situ hybridizationin bone and cartilage indicate that its expression marks some skeletaltissue elements able to differentiate into two skeletal celltypes—osteoblasts and chondrocytes. The terminal differentiation ofthese cells appears to be accompanied by down-regulation of CMF608expression. The latter observation is supported by the peculiar temporalpattern of CMF608 expression in primary cultures of osteogenic cellsisolated from calvaria bones of rat fetuses. In these cultures,expression was revealed by in situ hybridization in the vast majority ofcells after one and two weeks of incubation in vitro. Three and fourweek old cultures showing signs of ossification contained no CMF608expressing cells. Significantly, no hybridization signal was found onsections of multitissue block hybridized to CMF608 probe suggesting highspecificity of this gene expression for the skeletal tissue in adultorganisms.

[0134] In situ hybridization study of embryonic sections demonstratedthat at 12.5 dpc weak hybridization signal can be discerned in somemesenchymal cells in several locations throughout the embryonic body.The most prominent signal is found in the head in loose mesenchymaltissue surrounding the olfactory epithelium and underlying the surfaceepithelium of nose tip. Other mesenchymal cells in the head also showhybridization signal: non-cartilaginous part of basisphenoid boneprimordium and mesenchyme surrounding the dental laminae (toothprimordia) in the mandible.

[0135] In the trunk, expression can be detected in less developedvertebrae primordia in the thoraco-lumbar region. The hybridizationsignal here marks the condensed portion of sclerotomes. Another area ofthe trunk showing hybridization signal is comprised of a thin layer ofmesenchymal cells in the anterior part of thoracic body wall.

[0136] At later stages of development, 14.5 and 16.5 dpc, probe CMF608gave no hybridization signal. Thus, it appears that during embryonicdevelopment the CMF608 gene is transiently expressed by at least somemesenchymal and skeleton-forming cells. This expression isdown-regulated at later stages of development. More detailed study oflate embryonic and postnatal stages of development reveals the timing ofappearance of CMF608 expressing cells in bone tissue.

EXAMPLE 2 Isolation of Rat OCP

[0137] Primary rat calvaria cells grown on elastic membranes that werestretched for 20 minutes provided a model system for a stimulator ofbone formation following mechanical force. Gene expression patterns werecompared before and after the application of mechanical force.

[0138] OCP expression was upregulated approximately 3-fold by mechanicalforce. This was detected both by microarray analysis and by Northernblot analysis using poly (A)+ RNA from rat calvaria cells before andafter the mechanical stress. In rat calvaria primary cells and in ratbone extract this gene was expressed as a main RNA species ofapproximately 8.9 kb and a minor RNA transcript of approximately 9 kb.The hybridization signal was not detected in any other rat RNA fromvarious tissue sources, including testis, colon, intestine, kidney,stomach, thymus, lung, uterus, heart, brain, liver, eye, and lymph node.

[0139] The partial OCP rat cDNA clone (4007 bp long) isolated from a ratcalvaria cI)NA phage library was found to contain a 3356 bp open readingframe closed at the 3′ end. Comparison to public mouse databasesrevealed no sequence homologues. A complete OCP rat cDNA clone wasisolated from the rat calvaria cDNA library by a combination of 5′ RACEtechnique (Clontech), RT-PCR of 5′ cDNA fragments, and ligation of thelatter products to the original 3′ clone. The full rat cDNA clone thatwas generated (shown in FIG. 1 and pCDNA3.1-608, in FIG. 2) wassequenced, and no mutations were found. The full sequence stretch is8883 bp long and contains an ORF (rit 575-8366) for a 2597 amino acidresidue protein. FIG. 3. The cDNA does not contain a polyadenylationsite, but contains a 3′ poly A stretch.

[0140] CMF608 encodes a large protein that appears to be a part of theextra-cellular matrix. The gene may be actively involved in supportingosteoblast differentiation. Another option is that it is expressed inregions were remodeling takes place. Such an hypothesis is alsocompatible with a role in directing osteoclast action and thus it may bea target for inhibition by small molecules.

[0141] In normal bone formation, activation of osteoblasts leads tosecretion of various factors that attract osteoclast precursors ormature osteoclasts to the sites of bone formation to initiate theprocess of bone resorption. In normal bone formation both functions arebalanced. Imbalance to any side causes either osteitis deformans(osteoblast function overwhelms) or osteoporosis (osteoclast functionoverwhelms).

[0142] Among known osteoblast activators—mechanical force stimulation—isactually applied in the present model. As proof of principle, increasedexpression of several genes known to respond to mechanical stress bytranscriptional upregulation were found. They include tenascin,endothelin and possibly trombospondin.

EXAMPLE 3 Full-length OCP cDNA Construction and Expression

[0143] TNT (transcription—translation) assays were performed accordingto the manufacturer's instructions (Promega—TNT coupled reticulocytelysate systems), using specific fragments taken from various regions ofthe gene. In all assays a clear translation product was observed. FIG.4. The following fragments were tested: TNT products Frag. LocationFragment size (bp) Translation product size (kD) Promoter 1  134-21472013 73 T7 2 3912-5014 1102 40 ″ 3  574-1513  939 34 ″

EXAMPLE 4 The Mouse OCP Gene

[0144] Two mouse genomic Bac clones containing the mouse OCP genepromoter region and part of the coding region were identified, based ontheir partial homology to the 5′UTR region of the rat-608 CDNA. Theseclones (23-261L4 and 23-241H7 with ˜200Kb average insert length) werebought from TIGR. FIGS. 5 and 6.

[0145] Specific primers for the amplification of a part of the mouse-OCPpromoter region were designed and used for PCR screening of a mousegenomic phage library (performed by Lexicon Genetics Inc. for theApplicants). One phage clone containing part of the genomic region ofthe mouse 608 gene was detected and completely sequenced. The length ofthis clone was reported to be 11,963 bp. Parts of the physical “Lexicon”clone were re-sequenced by the inventors and corrections were made. Theresequenced clone (FIG. 7) is 11967 bp long. Exon-location prediction(FIG. 8) was performed by the Applicant company's Bioinformatics unitbased on the alignment of the mouse genomic and the rat cDNA sequences.FIGS. 9 and 10, respectively.

EXAMPLE 5 The Human OCP Gene

[0146] On the nucleotide level, the rat OCP cDNA sequence is homologousto the human genomic DNA sequence located on chromosome 3. Based on thehomology and bioinformatic analysis (FIGS. 10 and 11), a putative cDNAsequence was generated.

[0147]FIG. 12. The highest similarity is evident between nt 1-1965(1-655 a.a); 2179-2337 (727-779 a.a); and 4894-7833 (1635 a.a.-end) aspresented in the table shown in FIG. 13. On the protein level, nohomologues were found in the data bank.

EXAMPLE 6 The Deduced OCP Protein

[0148] The deduced OCP protein was generated following the alignment(FIGS. 14-16) of the rat, mouse and human cDNA sequences (FIGS. 1, 7 and12, respectively) and the equivalent rat, mouse and human amino acidsequences (FIGS. 3, 21 and 22, respectively).

[0149] The deduced OCP protein contains the following features (FIG.18):

[0150] a. a cleavable, well-defined N-terminal signal peptide (aa 1-28);

[0151] b. a leucine-rich repeat region (aa 28-280). This region can bedivided into N-terminal and C-terminal domains of leucine-rich repeats(aa 28-61 and 219-280, respectively). Between them, there are sixleucine-rich repeat outliers (aa 74-96, 98-120, 122-144, 146-168,178-200, 202-224). Leucine rich repeats are usually found inextracellular portions of a number of proteins with diverse functions.These repeats are thought to be involved in protein-proteininteractions. Each leucine-rich repeat is composed of β-sheet andα-helix. Such units form elongated non-globular structures;

[0152] c. twelve immunoglobulin C-2 type repeats at amino acid positions488-558, 568-652, 1635-1704, 1732-1801, 1829-1898, 1928-1997, 2025-2100,2128-2194, 2233-2294, 2324-2392, 2419-2487, 2515-2586. Thus, two Ig-likerepeats are found immediately downstream of a leucine-rich region, whilethe remaining 10 repeats are clustered at the protein's C-terminus.Immunoglobulin C-2 type repeats are involved in protein—proteininteraction and are usually found in extracellular protein portions;

[0153] d. no transmembrane domain; and

[0154] e. 5 nuclear localization domains (NLS) at: 724, 747, 1026, 1346and 1618.

[0155] These observations indicate that OCP belongs to the Igsuperfamily. OCP is a serine-rich protein (10.3% versus av. 6.3%), witha central nuclear prediction domain and an N-terminal extracellularprediction domain.

EXAMPLE 7 Bone Fracture Healing

[0156] Expression of 608 RNA is bone-specific. Moreover, it seems to bespecific to bone progenitors (as judged by their location in bone andinvolvement in normal bone modeling and remodeling processes) that donot yet express the known bone-specific markers. To further prove therelevance of 608-expressing cells to osteogenic lineage, the patterns of608 expression in the animal model of bone fracture healing that implythe activation of bone formation processes were studied.

[0157] The sequence of physiological events following bone fracture isnow relatively well understood. Healing takes place in threephases—inflammatory, reparative and remodeling. In each phase certaincells predominate and specific histological and biochemical events areobserved. Although these phases are referred to separately, it is wellknown that events described in one phase persist into the next andevents apparent in a subsequent phase begin before this particular phasepredominates. These events have been described over the years ininvestigative reports and review articles. Ham (1969) In, Histology, 6thed. Philadelphia, Lippincott, p. 441; and Urist and and Johnson (1943)J. Bone Joint Surg. 25:375.

[0158] During the first phase immediately following fracture (theinflammatory phase), wide-spread vasodilatation and exudation of plasmalead to the acute edema visible in the region of a fresh fracture. Acuteinflammatory cells migrate to the region, as do polymorphonuclearleukocytes and then macrophages. The cells that participate directly infracture repair during the second phase (the reparative phase), are ofmesenchymal origin and are pluripotent. These cells form collagen,cartilage and bone. Some cells are derived from the cambium layer of theperiosteum and form the earliest bone. Endosteal cells also participate.However, the majority of cells directly taking part in fracture healingenter the fracture site with the granulation tissue that invades theregion from surrounding vessels. Trueta (1963) J. Bone Joint Surg.45:402. Note that the entire vascular bed of an extremity enlargesshortly after the fracture has occurred but the osteogenic response islimited largely to the zones surrounding the fracture itself. Wray(1963) Angiol. 14:134.

[0159] The invading cells produce tissue known as “callus” (made up offibrous tissue, cartilage, and young, immature fibrous bone), rapidlyenveloping the ends of the bone, with a resulting gradual increase instability of the fracture fragments. Cartilage thus formed willeventually be resorbed by a process that is indistinguishable except forits lack of organization from endochondral bone formation. Bone will beformed by those cells having an adequate oxygen supply and subjected tothe relevant mechanical stimuli.

[0160] Early in the repair process, cartilage formation predominates andglycosaminoglycans are found in high concentrations. Later, boneformation is more obvious. As this phase of repair takes place, the boneends graually become enveloped in a mass of callus containing increasingamounts of bone. In the middle of the reparative phase the remodelingphase begins, with resorption of portions of the callus and the layingdown of trabecular bone along lines of stress. Finally, exerciseincreases the rate of bone repair. Heikkinen et al. Scand J. Clin. Lab.Invest. 25(suppl 113):32. In situ hybridization results have shown thatOCP expression is confined to very specific regions where bone andcartilage formation is initiated.

[0161] In order to find out if OCP expression is induced in an animalmodel of bone fracture healing, a standard midshaft fracture was createdin rat femur by means of a blunt guillotine, driven by a dropped weight.Bonnarens et al. (1984) Orthop. Res. 2:97-101. One, 2, 3 and 4week-fractured bones were excised, fixed in buffered formalin,decalcified in EDTA solution and embedded in paraffin. All sections werehybridized with the OCP probe. The in-situ hybridization results showthat a strong hybridization signal was apparent during the first andsecond weeks of fracture healing in the highly vascularized areas of theconnective tissue within the callus (FIGS. 26-28), the endosteum (FIG.29), the woven bone (FIG. 30) and the periosteum (FIG. 31). Theperiosteum is regarded as a source of undifferentiated progenitorsparticipating in callus formation at the site of bone fracture. Thehybridization signal disappeared slowly during further differentiationstages of fracture healing (three and four weeks) and was retained onlyin the vascularized connective tissue. FIG. 32 displays brightfield(left) and darkfield (right) microphotographs of a section of fracturedbone healed for 4 weeks. In these later healing stages, the maturecallus tissue was found to be comprised mainly by cancellous boneundergoing remodeling into compact bone, with little if any cartilage orwoven bone present. The volume of the vascularized periosteal tissue isdecreased but multiple cells in the periosteal tissue area of activeremodeling of the cancellous bone covering the callus, showhybridization signal. This tissue covers the center of the callus and isalso entrapped within the bone. See FIGS. 32 and 33. The box in FIG. 32is enlarged in FIG. 33. As in the earlier stages, no hybridizationsignal was found in chondrocytes and osteoblasts. FIGS. 27 and 33.Several OCP expressing cells are concentrated in the vascular tissuethat fills the cavities resulting from osteoclast activity (marked byasterisks).

[0162] Fractures in the young heal rapidly, while adult bone fracturesheal slowly. The cause is a slower recruitment of specificchondro-/osteo-progenitors for the reparative process. Denervationretards fracture healing by diminishing the stress across the fracturesite, while mechanical stress increases the rate of repair probably byincreasing the proliferation and differentiation of specific boneprogenitor cells and as a result, accelerates the rate of boneformation. The above results confirm our conclusions (see alsohereunder) that OCP is most probably involved in induction of corticaland trabecular bone formation and remodeling, endochondral bone growthduring development, and bone repair processes. In addition, there isstrong evidence that OCP expression is tightly regulated, and inducedduring the earliest stages of bone fracture repair whenosteo-/chondro-progenitor cells are recruited. This observation suggeststhat OCP plays a role in this process.

[0163] Taking into account the pattern of 608 expression during theprocess of bone fracture healing, it is tempting to suggest that608-positive precursor cells are involved not only in remodeling ofintact bone but also in the repair processes of the fractured bone aswell.

EXAMPLE 8 OCP Transcriptional Regulation

[0164] In order to clone the longest possible fragment which willcontain the OCP regulatory region/s, bacs L4 and H7 were restricted withthree different enzymes: BamHI, Bgl II and SauIIIA. The resultingfragments were cloned into the BamHI site of pKS. Ligation mixes weretransformed into bacteria (E. coli—DH5a) and 1720 colonies were platedonto nitrocellulose filters which were screened with ³²P-labeled PCRfragment spanning the mouse-OCP-exon1. Positive colonies were isolated.

[0165] Two identical clones, 14C10 and 15E11, contained the largestinserts (BamHI derived ˜13Kb inserts). The structure of the insertcompared to the “Lexicon” clone previously mentioned is illustrated inFIG. 45. The 14C10 clone is longer than the OCP “Lexicon” clone by ˜8Kbat the 5′end.

[0166] a) Cloning of Mouse OCP Promoter and UTR Upstream to the ReporterGene—EGFP

[0167] The 1.4Kb genomic region of the mouse OCP gene, flanked by BamHIsite (nuc 5098 of the “Lexicon” clone which is the start site of clonep14C10) and the first ATG codon (first nucleotide of exon 2), wassynthesized by genomic PCR using the “Lexicon” clone as template andpre-designed primers: 5′primer (For1) located upstream to the BamHI site(nucleotides 4587-4611 of the Lexicon clone) and 3′ primer (Rev 2)located immediately upstream to the first ATG (nucleotides 6560-6540 ofthe Lexicon clone) and tailed by a NotI site. The PCR product was cut byBamHI and NotI and the resulting 1.4Kb fragment was ligated to pMCSEinto BamHI/NotI sites upstream to the EGFP reporter gene. The resultingclone was designated pMCSIEm608prm1.4.

[0168] Clone p14C10 was cut by XbaI and BamHI and the excised 4.088Kbfragment was ligated into the BamHI and XbaI sites of pMCSIEm608prm1.4,upstream to the 1.4Kb insert. The resulting clone (shown in FIG. 46) wasdesignated pMCSIEm608prm5.5 and contains 5552 nucleotides of the mouse608 promoter and UTR upstream to EGFP. The insert of pMCSIEm608prm5.5clone was completely sequenced, as can be seen in FIG. 47.

[0169] The whole 13Kb insert of p14C10 was excised by BamHI and ligatedupstream to the 1.4Kb insert of of pMCSIEm608prm1.4 into the BamHI site.The resulting construct, pMCSIEm608prm14.5 contains a 14.5Kb fragment ofthe mouse-OCP promoter and UTR upstream to EGFP.

[0170] b) Transient Transfection Results

[0171] The two constructs, pMCSIEm608prm5.5 and pMCSIEm608prm14.5, wereinjected to fertilized mouse eggs and two weeks old transgenic andcontrol mice were sacrificed for the detection of GFP activity incalvaria and long bones. No specific fluorescence was detected, partlybecause of background fluorescence from various tissues and partlybecause of the cellular specificity of OCP expression. Therefore, theinventors decided to use the more sensitive luciferase gene as thereporter gene.

[0172] c) Clonino Mouse OCP Promoter and UTR Upstream to the ReporterGene-luciferase

[0173] Both inserts of pMCSIEm608prm5.5 and of pMCSIEm608prm14.5 werealso cloned upstream to luciferase, in Promega's pGL3-Basic vector. The5.5Kb insert of pMCSIEm608prm5.5 was excised by EcoRV and XbaI andligated to SmaI and NheI sites of pGL3-Basic vector. The resulting cloneis designated pGL3basicm608prm5.5.

[0174] Plasmid pMCSIEm608prm14.5 was restricted by NotI and the cohesiveends of the linearized plasmid were filled and turned into blunt ends.The 14.5Kb insert was then excised by cutting the linear plasmid bySalI. The purified 14.5Kb fragment was ligated to the XhoI and HindIII(filled in) sites of pGL3-basic upstream to the luciferase gene tocreate the construct designated pGL3basicm608prm14.5. FIG. 48 depicts4610 bp that have been sequenced. d) Transient Transfection Results

[0175] At this stage transient transfection of both constructs toprimary calvaria cells, resulted in 10-fold expression only uponpMCSIEm608prm14.5 transfection. No enhanced promoter activity wasobserved upon pMCSIEm608prm5.5 transfection. These observations suggestthat the region between the 5′end of pMCSIEm608prm14.5 and the 5′end ofpMCSIEm608prm5.5 is necessary for full promoter activity. Furtheranalysis is in process to detect all the sequences that are necessaryand sufficient for maximal promoter activity and tissue specific OCPinduction or repression in various cell systems.

[0176] e) Analysis of TF Binding DNA Elements Common to Mouse and HumanOCP

[0177] Known transcription factor (TF) binding DNA elements wereanalyzed for similarity upstream of human and mouse OCP ATG using theDiAlign program of Genomatix GmbH. The genomic pieces used are theproprietary mouse genomic OCP and reverse complement of AC024886 92001to 111090. The locations of the ATG in these DNA pieces are:

[0178] 575 on rat cDNA

[0179] *6521 on mouse genomic

[0180] *3381 on the piece extracted from human genomic DNA AC0024886 14elements were extracted in this procedure and analyzed for transcriptionbinding motifs using the MatInspector.

[0181] Some of the main “master gene” binding sites are illustrated inFIG. 49. Among them are the osteoblast-/chondrocyte-specific Cbfalfactor; the chondrocyte-specific SOX 9 factor; the myoblast-specificMyo-D and Myo-F factors; the brain- and bone-specific WT1; Egr 3 and Egr2 factors (Egr superfamily); the vitamin D-responsive (VDR) factor; theadipocyte-specific PPAR factor; and the ubiquitous activator SP 1.

EXAMPLE 9 Expression Pattern and Regulation of Gene 608 Expression ofGene 608 in Regard to other Osteogenic Lineage Markers

[0182] Expression of gene 608 was tested in primary cells and in celllines with regard to expression of various markers of osteogenic andchondrogenic lineages. The results of this analysis are summarized inthe following table and showed that expression of 608 is restricted tocommitted early osteoprogenitor cells. Cells 608 Collagen I Collagen IIAlk. Phos. Osteocalcin Cbfa1 Osteopontin STO − − + − + + + (fibroblasts)ROS − − − + + +/− + (osteosarcoma) MC3T3 (pre- + − − + + + +osteoblasts) C2C12 (pre- − − − − + − + myoblasts) C6 − − (glioma)Calvaria mouse + + Calvaria rat + + C3H10T1/2 − − + − + − + (mesenchymalstem cells)

EXAMPLE 10 OCP Expression is Mechanically Induced in MC3T3 E1 Cells

[0183] OCP transcription was detected by RT-PCR in mouse calvaria cells,U20S cells (human osteosarcoma cell line), and human embryonal bone.FIG. 24. OCP was initially discovered as being upregulated duringmechanical stress in calvaria cells. In the present invention, wedemonstrate that the influence of mechanical stress on OCP expressioncan be reproduced in another cell system using a different type ofmechanical stimulation. In serum-deprived MC3T3-E1 pre-osteoblasticcells, mechanical stimulation caused by mild (287× g) centrifugationmarkedly induced OCP mRNA accumulation. FIG. 25. Other osteoblasticmarker genes (osteopontin, ALP (staining—not shown) and Cbfal) weretranscriptionally augmented by this procedure. FIG. 25. The RT-PCRproduct of a non-osteoblastic marker gene (GAP-DH) was used as a controlto compare RNA levels between samples. No increased expression wasnoticed when the latter primers were used. No expression was detected innon-osteoblastic cells (FIG. 24), suggesting that OCP expression isspecifically induced in osteogenesis.

EXAMPLE 11 OCP Induction During Endochondral Growth—in SituHybridization Analysis

[0184] Our previous results demonstrated that OCP is expressed duringadult mice bone modeling and remodeling. The expression was restrictedto the following regions:

[0185] 1 perichondrium

[0186] 2 periosteum

[0187] 3 active remodeling and modeling regions

[0188] 4 perivascular connective tissue

[0189] 5 articular cartilage covering cells

[0190] 6 embryo-condensed mesenchymal cells—head, vertebrae and trunk

[0191] 7 ectopic bone formation

[0192] No previous observations suggest any role for OCP in bonedevelopment or initiation of endochondral ossification (longitudinalgrowth of long bones). Thus, the expression pattern of OCP by in situhybridization on sections of bones from 1 week old mice was analyzed. Atthis stage of bone development, osteogenesis starts within the epiphysis(secondary ossification center). The hind limb skeleton of 1 week oldrat pups (femur together with tibia) was fixed in buffered formalin andlongitudinal sections of decalcified tissue were processed for in situhybridization according to standard in-house protocol. Autoradiographswere developed, stained with hematoxylin-eosin and studied undermicroscope using brightfield and darkfield illumination.

[0193] A strong fluorescence signal was observed all over the secondossification center using OCP probes. FIG. 27. In addition, thehybridization signal delineates periosteal and perichondrial tissue in away similar to that found earlier in adult bones. Surrounding maturechondrocytes displayed no signal. A very faint signal was observed usingthe osteocalcin probe which is a marker of mature osteoblasts.

[0194] In conclusion, OCP is expressed in osteoprogenitor cells thatinitiate eridochondral ossification during bone development.

EXAMPLE 12 In Vivo Regulation by Stimuli Either Promoting or SuppressingBone Formation: Estrogen Administration, Blood Loss and SciaticNeurotomy

[0195] Osteogenic cells are believed to derive from precursor cellspresent in the marrow stroma and along the bone surface. Blood loss, acondition that stimulates hemopoietic stem cells, activatesosteoprogenitor cells in the bone marrow and initiates a systemicosteogenic response. High-dose estrogen administration also increases denovo medullary bone formation possibly via stimulation of generation ofosteoblasts from bone marrow osteoprogenitor cells. In contrast,skeletal unweighting, whether due to space-flight, prolonged bed-rest,paralysis or cast immobilization leads to bone loss in humans andlaboratory animal models. To detect alteration in OCP expression patternfollowing the above procedures, the following experiments were performedon two month old mice:

[0196] estrogen administration (500 μg/animal/week),

[0197] bleeding (withdrawing approximately 1.6% body weight),

[0198] unilateral (right limb) sciatic neurotomy,

[0199] control groups for each treatment

[0200] Total RNA was extracted from long bones after two-day treatmentand RT-PCR using OCP-specific primers was performed. The resultsdemonstrate that OCP expression was highly enhanced following blood lossand estrogen administration, while down-regulation was observedfollowing sciatic neurotomy. FIG. 29.

[0201] By having a unique cell marker (OCP) we can show that the aboveprocedures induce or reduce bone formation by increasing or decreasingthe number of osteoprogenitor cells. The above results suggest once morethat OCP is a major member of a group of “bone specific genes” thatregulate the accumulation of bone specific precursor cells.

EXAMPLE 13 OCP Induction During Osteoblastic Differentiation of BoneMarrow Stroma Cells

[0202] Bone formation should be augmented in trabecular bone andcortical bone in osteoporotic patients. We have previously detected OCPexpression in periosteum and endosteum (surrounding the cortical bone)but no signal was apparent in bone marrow cells. The latter cellsnormally differentiate to mature osteoblasts embedded in the trabecularand cortical bone matrix.

[0203] To further assess OCP expression in bone marrow progenitor cells,the inventors extracted total RNA from mouse and rat bone marrowimmediately after obtaining it and after cultivation for up to 15 daysin culture. No OCP-specific RT-PCR product was detected with RNA fromfreshly obtained bone marrow (both in adherent and non-adherent) cells.However, a faint signal was found after 5 days in culture, and it wasfurther enhanced when RNA from cells grown for 15 days in culture wasused. ALP (alkaline phosphatase) expression (an osteoblastic marker) wasalso found to be enhanced after 15 days. At both time points, adherentand non-adherent cells were reseeded, and RNA extractions were prepared5 and 15 days later. A stronger RT-PCR product was observed with RNAextracted from originally adherent cells, suggesting the existence ofless mature progenitors in the non-adherent population of bone marrowcells. The RT-PCR product of a non-osteoblastic marker gene (GAP-DH) wasused as a control to compare RNA levels between samples.

[0204] In conclusion, bone marrow progenitor cells do not express OCP,but differentiate to more committed cells that do express this gene.

EXAMPLE 14 OCP Induction During Mesenchymal Cell Differentiation TowardsOsteogenesis

[0205] Mesenchymal stem cells (MSC) are multipotent, self-renewing cellpopulations which undergo differentiation and commitment to give rise tomonopotent cells of specified lineages, such as osteoblasts. Themechanisms of commitment and self-renewal are not fully understood, butmay be regulated by factors such as Bone Morphogenetic Proteins (BMPs),differentiation factors such as retinoic acid (RA) and steroid hormonessuch as glucocorticoids. Furthermore, BMP and RA act synergistically tostimulate osteoblastic commitment and cell proliferation.

[0206] In order to find out if OCP expression is induced uponosteoblastic commitment, quiescent C3H10T½ murine MSC cultures werestimulated with BMP and RA for 24 hours and cultured in full medium forfurther 3 days. RNA was extracted from non-treated cells as well as fromcells harvested at 24hrs, 48hrs and 72hrs after the beginning of thetreatment, and used for RT-PCR analysis with OCP-specific primers. Inparallel, cells were stained for ALP to determine osteoblasticcommitment. While ALP staining was apparent only on day 3 (72hrs), OCPexpression was augmented by day 1 (24hrs), being undetectable innon-treated cultures. Further experiments have shown that even strongerALP staining and OCP expression were observed on day 6 followingproliferation and further differentiation of osteoprogenitor cells. FIG.26.

[0207] These results demonstrate that upon osteoblastic commitment ofMSCs, OCP expression is “switched-on” before the commencement of ALPexpression, suggesting that this candidate is the earliest marker geneof osteoprogeniter cells found to date. It should be noted that ourprevious in situ hybridization results also demonstrated the presence ofOCP transcripts only in very early chondro-/osteo-progenitor cells.These cells did not express ALP, and more mature ALP positive cells (inthe trabecular bone) were OCP negative.

EXAMPLE 15 OCP Induction During Differentiation Switch of Pre-myoblaststo Osteoblasts

[0208] Pre-myoblastic cells (C2C12) give rise to mature myoblasts. Aswith C3H10T½, the administration of BMP and RA to these cells can induceosteoblastic differentiation. To investigate the expression pattern ofOCP during this differential switch we introduced BMP and RA to C2C12cells and analyzed cell fate and expression pattern as above (forC3H10T½ cells). As expected OCP and ALP expression were induced 24hrspost-BMP introduction. FIG. 26.

[0209] These assays once more demonstrate the involvement of OCP in theearly stages of osteogenesis.

EXAMPLE 16 OCP Role in Osteogenesis

[0210] The ultimate test for the role of OCP as a crucial factor thatinduces osteoblast-related genes is its ability to up-regulate thesegenes in pre-osteoblastic and osteoblastic cells. In primary calvariacells, transient transfection with a CMV promoter-driven OCP constructsignificantly up-regulated the expression of the osteogenic lineagemarker ALP. FIG. 34 illustrates the induction in ALP staining. Transienttransfections of two smaller deletion constructs of the OCP gene alsogave the same induction (FIG. 35), suggesting that the N-terminal 403amino acid protein stretch (which contains a signal peptide) isnecessary and sufficient to augment osteoblastic proliferation anddifferentiation. In addition, stable transfection of OCP to ROS 17/2.8(differentiating osteoblast cell line) cells, also substantiallyupregulated ALP and BSP expression, while repressing Cbfa1 transcription(Cbfa1 is known to be expressed early in the osteoblast lineage and tobe transcriptionally downregulated during cellular aging ofosteoblasts). FIG. 36. In addition, marked increase in osteoblasticproliferation was observed. FIG. 37.

[0211] Further experiments have shown that the osteogenic effect of OCPexpression in calvaria cells is non-cellautonomous. In a co-cultivationassay where OCP-transfected calvaria cells were cultured in the presenceof nontransfected calvaria cells (that were grown on a milliporefilter), the osteogenic induction effect was also evident as wasillustrated in FIG. 38. The non-transfected cells that were cultured inthe presence of C)CP-transfected cells retained elevated ALP activitycompared to control assays. No similar effects were observed upontransfection to the pluripotent progenitor C3H10T½ cells that candifferentiate to myoblasts, osteoblasts, adipocytes or chondrocytes orto C2C12 pre-myoblast cells.

[0212] These results provide compelling evidence that OCP is anessential factor required for the initiation of the signaling cascadethat leads to sequential expression of other phenotype-specific genescommitted to the osteogenic lineage. In addition, these results supportaccumulation of an OCP-dependent osteogenesis factor that seems to actas a secreted factor. We have no data yet as to whether this factor isthe OCP product or an OCP-induced factor.

EXAMPLE 17 Bone Culture Assays

[0213] To further confirm the involvement of OCP in bone formation, weperformed organ culture of E16 mouse embryonal limbs. The limb boneswere stained with Alizarin Red following 6 days of culture to comparebone calcification rate. When the E16 mouse embryonal limbs werecocultivated with OCP-transfected calvaria cells, both endochondral andmembranous ossification were enhanced as illustrated in FIG. 42. Incontrast to the control limbs (cocultivated with vector-transfectedcalvaria cells), the OCP transfection to calvaria cells resulted in theformation of bones that are longer and wider in their proximal anddistal extremities. Thus, we have shown that the osteogenic inducingeffect of OCP that was observed in vitro, can be also demonstrated exvivo by the induction of bone formation in cartilage bone rudiments. Therole of OCP in bone rudiments probably mimics its role in endochondralossification and bone development of mouse fetuses.

EXAMPLE 18 Oc-OCP Transgenic Mice

[0214] To verify the results presented in the present invention, theinventors generated transgenic mice in which 608 expression is inducedin mature osteoblasts by coupling the OCP cDNA to the osteocalcin (Oc)promoter. Construction of the pOC-608 vector.

[0215] The Oc promoter was amplified using primers according to theliterature. The promoter was taken from plasmid pSROCAT (Lian et al.(1989) Proc. Natl. Acad. Sci. U.S.A. 86:1143-1147) using SmaI andHindIII (blunted) and sub-cloned into the blunted BamHI and XbaI sitesof the vector pMCS-SV producing the vector pOC-NSV.

[0216] The CMF608 Flag fragment was isolated from the pCDA3.1-608construct (FIG. 2) after NotI and SpeI digest. The fragment wassub-cloned into the NotI-SpeI sites of the pOC-MCS vector. The constructwas verified by extensive sequencing. FIG. 43.

[0217] Preparation of DNA for Microinjection

[0218] For the preparation of the DNA insert for microinjection theplasmid was digested with AscI (cuts at bp 43 and bp 10595). The ˜10.6Kbfragment was isolated from agarose gel using the Qiaex II kit (QiagenCat No. 20021) and then purified over an Elutip-D column (Schleicher &Schuell Cat. No. NA010/1).

[0219] Derivation of Transgenic Mice

[0220] The DNA was dissolved in a pure Tris/EDTA microinjection solutionand adjusted to a concentration of 2 ng/μl. Standard pronuclearmicroinjection into fertilized eggs from the FVB/N strain and embryotransfer into ICR foster mothers was performed as described in theliterature. See, Manipulating the Mouse Embryo, Hogan, Beddington,Constantini and Lacy, Cold Spring Harbor Laboratory Press.

[0221] Embryo Recovery

[0222] Foster mothers were sacrificed by cervical dislocation at day 18post-embryo transfer. Embryos were recovered and placentas were takenfor DNA preparation and analysis of the presence of the injectedOC608-Flag DNA in the mouse genome.

[0223] Genomic DNA Analysis

[0224] Mouse genomic DNA was recovered from the placenta using standardprocedures. Laired et al. (1991) Nucl. Acids Res. 19:4293. Genomic DNAwas digested with EcoRV, separated on 1% agarose gel and blotted ontoNytran nylon membranes (Schleicher & Schuell). The blots were hybridizedwith a SV40 intr&polA labeled probe (see map) overnight and washed thefollowing day. Membranes were exposed to X-ray film and developed after24 and 48 hours. FIG. 44.

[0225] OCP Exogenic RNA Expression Analysis

[0226] To determine which of the transgenic embryos expressed theexogenic OCP, total RNA was isolated from the hind legs according to themanufacturer's instructions (EZ-RNA, total RNA isolation kit, Biologicalindustries). 5 μg of total RNA was assayed by RT-PCR according to themanufacturer's instructions (GIBCO BRL SuperScript™ II). As, a negativecontrol, RT was omitted. PCR was performed for 30 cycles (1 min at 94°C., 1 min at 59° C.,and 2 min at 72° C.), using Taq polymerase (Promega)and either exogenic OCP or GapDH primers that amplify cDNA products of1020 bp and 450 bp, respectively.

[0227] The following primers were used for exogenic OCP detection:

[0228] Forward: 5′ GCACTGAACTGCTCTGTGGAT 3′ (SEQ ID NO:22); and

[0229] Reverse: 5′ CCACAGAAGTAAGGTTCCTTCAC 3′ (SEQ ID NO:23).

[0230] Reaction products (5 μl per lane) were electrophoresed in 1.5%agarose and stained in ethidium bromide. As illustrated in FIG. 45,similar amounts of GapDH transcripts were detected in all RNA samplesfrom all tested embryos, indicating that differences in OCP transcriptabundance did not reflect variation in the efficiency of the RTreaction. In addition, no GapDH PCR products were detected in any RNAsamples when RT was omitted. The results show that OCP was expressed byosteoblasts under osteocalcin promoter transcriptional regulation onlyin embryo numbers 5, 7, 9, 11, 15, 21, 26 and 27. FIG. 45.

[0231] Characterization of Bone Growth in Osteocalcin Promoter—608Transgenic Embryos

[0232] The results illustrated in FIGS. 46-48, suggest thatover-expression of OCP during mice embryonal development (E17) resultsin increased endochondral (longitudinal) and membranous ossification oflong bones and increased membranous ossification of calvaria flat bones.Summarizing the above results shows that this phenotype is causedprimarily by a profound increase in osteoblastic proliferation,differentiation and finally osteoblast activity.

EXAMPLE 19

[0233] Creation of a Readout System

[0234] A readout system is created to identify small molecules that caneither activate or inactivate OCP bone-precursor-specific promoter.

EXAMPLE 20

[0235] Bioinformatic Analysis of Human 608

[0236] A DNA sequence encoding a fragment of human OCP named AC024886 isfound in htgs database but not in nt. There is no genomic DNAcorresponding to the rat cDNA. Alignment of AC024886 against the ratcDNA using BLAST shows two areas of long alignment (and several shorterareas):

[0237] 1. cDNA: 6462-8186

[0238] Genomic: 89228-90952 plus/plus orientation: 81% identity

[0239] 2. cDNA: 5581-6451

[0240] Genomic: 107710-106840 plus/minus orientation: 80% identity

[0241] Thus AC024886 is wrongly assembled in the region upstream ofposition 6462 (according to the rat cDNA), it is in the incorrectorientation. Using the incorrect orientation provides incorrect codingsequence and does not yield the human OCP protein.

[0242] The Genbank report on AC024886 is as follows: LOCUS AC024886175319 bp DNA HTG 06-SEP-2000 DEFINITION Homo sapiens chromosome 3 cloneRP11-25K24, WORKING DRAFT SEQUENCE, 9 unordered pieces. ACCESSIONAC024886 VERSION AC024886.10 GI:9438330 KEYWORDS HTG; HTGS₋PHASE1;HTGS₋DRAFT. SOURCE human. # it is available and the accession numberwill be preserved.

[0243] a. Mapping Human Genomic 608 Exons

[0244] Ten exons were mapped on the rat cDNA sequence from base 107 to6451. Thus the first exon on the human genomic piece may be lacking. Thehuman genomic piece (AC024886) upstream (19090 bases) of base 6462 ofcDNA (reverse complement from base of AC024886 92001 to 111090) wascompared with the rat cDNA using the program ExonMapper of Genomatix. Inthe Table, base 1 is actually 1131 in the genomic piece used so that theactual genomic location starts at 91870.

[0245] Two additional exons were mapped on the rat cDNA sequence frombase 6462 to 8883. Thus bases 6452-6461 are lacking. The human genomicpiece used is from base 165,337 to 175667 (10,341 bases). The same typeof program was used to compare this sequence to the QBI genomic mouse608.

[0246] Connecting the exon/intron borders from the genomic sequencesyielded the predicted human and mouse cDNAs. The mouse and humanpredicted cDNAs were modified in order to allow frame shifts that allowa good multiple alignment of the human, mouse and rat proteins.Alignment was done using CLUSTALX and Pretty.

[0247] The cDNA modifications after the alignment of human cDNA to ratcDNA by GeneWise were as follows. In the following two tables, −xindicates a deletion of nucleotide x in the cDNA sequence; +x indicatesan insertion of nucleotide x in the cDNA sequence; and all changedpositions are in relation to the original sequence Position Change 1111−g 4154 −c 4538 +g 4730 −a 4744-5 −aa 4830 +c 4852 −g 4902 +t 4942 +c5370 +t 5387 −a 5395 +c

[0248] The corrections of frams-shifts in mouse 608 were as follows:Position Change  678 −c 1106 −a

[0249] Chromosomal Location on the Human Chromosome:

[0250] Two different types of data exist.

[0251] Genomic piece AC024886 has identity to the fragment identified asACCESSION D14436 as described by Fukui et al. (1994) Biochem. Biophys.Res. Commun. 201:894-901.

[0252] Alignment information:

[0253] Identities=315/335 (94%),

[0254] hrh1:4 −338

[0255] AC024886-41328

[0256] Hrh1 is mapped to chromosome 3 and to 3p25; and

[0257] b. Identity to STS at 3q. STS: 20-432 is identified as ACCESSIONG54370 and described by Joensuu et al. (2000) Genomics 63:409-416.

EXAMPLE 21 Polyclonal Antibody Preparation

[0258] Polyclonal antibodies specific to the whole 608 putative proteinare prepared by methods well-known in the art (the structure of 608resembles that of growth factor precursors). Polyclonal antibodies areidentified and the recombinant active form of 608 is prepared. Theactivities of the polyclonal antibodies are tested in vivo in mice. Theantibodies can be used for the identification of the active form of thisprotein which is likely to constitute a fraction of the 608 protein.

EXAMPLE 22 Stretch of Basic Amino Acids Found at the Boundary of the Ratand Human 608 Proteins, and its Implications

[0259] The homology between the rat and human N-terminal portions of the608 protein is especially significant within the first 250 amino acids.

[0260] At the boundary of this conserved region there is a completelyconserved stretch of basic amino acids: KCKKDR (aa 242-247 and 240-245,in rat and human proteins, respectively). Stretches of basic amino acidsfrequently serve as protease cleavage sites. The fact that such astretch is found on the boundary of more or less conserved sequences andthe fact that it occurs within the C-terminal LRR, a generally conserveddomain, suggests an underlying biological significance.

[0261] Accordingly, the 608 protein may undergo post-translationalprocessing through the cleavage of its highly conserved N-terminalportion and this portion may be an active part of the 608 protein orpossess at least part of its biological activities. Since the resulting˜25 kD protein preserves the signal peptide, it would be secreted.

[0262] To test whether the 25 kD cleavage product of the 608 protein isresponsible for the osteogenic activity of medium conditioned by608-transfected calvaria cells, we constructed a pcDNA vector containingthe N-terminal portion of rat 608 cDNA encoding amino acids 1-241 (notincluding the KCKKDR stretch) and transiently expressed it in ratcalvaria cells. The transfected cells were assayed for inducing boneformation both in co-cultured non-transfected calvaria cells and in exvivo cultured E16 mouse embryo (as described above). The results clearlyindicated that the secreted N-terminal portion of OCP was sufficient tostimulate osteogenesis in co-cultured cells and embryo bones.

[0263] The biologically active 25 kD N-terminal cleavage product of 608can thus be used for treatment and/or prevention of osteoporosis,fracture healing, bone elongation and periodontosis. As an indirectproduct (inhibition by either chemicals or by neutralizing mAbs), thefragment can be used for treatment and/or prevention of osteoarthritis,osteopetrosis, and osteosclerosis.

EXAMPLE 23 The Adlican Protein and Gene

[0264] Adlican is a recently described protein. Crowl and Luk (2000)Arthritis Biol. Res. Adlican, a proteoglycan, was derived from placenta.The full amino acid sequence of Adlican is disclosed and identified asAF245505.1:1.8487, and is hereby incorporated by reference into thisapplication. FIG. 51.

[0265] The structure of Adlican was analyzed using methods describedherein and found to have leucine-rich repeats and immunoglobulin regionssimilar to those of the OCP protein. The overall homology found betweenthe amino acid residues of the indicated regions in the two proteins, isas follows: OCP Adlican %  1-661  1-669 38.4  662-1629  670-1865 19.71630-2587 1866-2828 46.5   1-2587   1-2828 33.2

[0266] The invention therefor encompasses the use of Adlican in anymanner described herein for the OCP protein. These functions and useshave not been disclosed previously for Adlican. They include use ofAdlican, or a functional portion thereof, for preventing, treating orcontrolling osteoporosis, or for fracture healing, bone elongation ortreatment of osteopenia, periodontosis, bone fractures or low bonedensity or other factors causing or contributing to osteoporosis orsymptoms thereof or other conditions involving mechanical stress or lackthereof in a subject. As an indirect product (inhibition by eitherchemicals or by neutralizing mAbs), Adlican can be used for treatmentand/or prevention of osteoarthritis, osteopetrosis, and osteosclerosis.

[0267] The Adlican gene, or functional portions thereof, can likewise beused for any purpose described herein for an OCP gene. Compositionscomprising the Adlican gene, Adlican or antibodies specific for Adlicanand physiologically acceptable excipients are likewise encompassed bythe invention. Such excipients are known in the art and include saline,phosphate buffered saline and Ringer's solutions.

[0268] Having thus described in detail preferred embodiments of thepresent invention, it is to be understood that the invention defined bythe appended claims is not to be limited by particular details set forthin the above description as many apparent variations thereof arepossible without departing from the spirit or scope thereof.

1 25 1 8883 DNA Rattus species misc_feature (1)..(8883) ′n′ can be anynucleotide ′a′, ′c′, ′g′ or ′t′. 1 cgagagacga cagaaggtta cggctgcgagaagacgacag aagggtccag aaaaaggaaa 60 gtgctggagg ggagtgggga caaaagcagcgaccaagtga atgtcacttc agtgactgag 120 gccaggcaaa acgcgcggga aggattttgtgtagcttggg accctttcat agacactgat 180 gacacgttta cgcaaaatag aaatttgaggagaaacgcct gggccttcgg aaaggagtga 240 ttgattagta cttgcaagtt taggtgactttaaggagaac taactaatgt atactattga 300 gggaggagga agagcattac agagtttccagcagcagcag gaaagctttg gttaatttgg 360 aaatggatga tagcattaaa ataacagaagcgcctccagg tctctgaagc ttcagtcccc 420 cagctgaaag ccagaaaaga ctaagcccactaagcctttt gatccctttg gaagcaaaga 480 actttccttc cctggggtga agactctcctcagaagattt cctgtctctg cctatgttac 540 aagaggaatc aaaaccaaga cagaagagctcaggatgcag gtgagaggca gggaagtcag 600 cggcttgttg atctccctca ctgctgtctgcctggtggtc acccctggga gcagggcctg 660 tcctcgccgc tgtgcctgct atgtgcccacagaggtgcac tgtacatttc ggtacctgac 720 ctccatccca gatggcatcc cggccaatgtggaacgaata aatttaggat ataacagcct 780 tactagattg acagaaaacg actttgatggcctgagcaaa ctggagttac tcatgctgca 840 cagtaatggc attcacagag tcagtgacaagaccttctcg ggcttgcagt ccttgcaggt 900 cttaaaaatg agctataaca aagtccaaatcattcggaag gatactttct acggactcgg 960 gagcttggtc cggttgcacc tggatcacaacaacattgaa ttcatcaacc ctgaggcctt 1020 ttatggactt acctcgctcc gcttggtacatttagaagga aaccggctca caaagctcca 1080 tccagacaca tttgtctcat taagctatctccagatattt aaaacctctt tcattaagta 1140 cctgttcttg tctgataact tcctgacctccctcccaaaa gaaatggtct cctacatgcc 1200 aaacctagaa agcctgtatt tgcatggaaacccatggacc tgtgactgcc atttaaagtg 1260 gttgtctgag tggatgcagg gaaacccagatataataaaa tgcaagaaag acagaagctc 1320 ttccagtcct cagcaatgtc ccctttgcatgaaccccagg atctctaaag gcagaccctt 1380 tgctatggta ccatctggag ctttcctatgtacaaagcca accattgatc catcactgaa 1440 gtcaaagagc ctggttactc aggaggacaatggatctgcc tccacctcac ctcaagattt 1500 catagaaccc tttggctcct tgtctttgaacatgacanan ntntctggaa ataaggccga 1560 catggtctgt agtatccaaa agccatcaaggacatcacca actgcattca ctgaagaaaa 1620 tgactacatc atgctaaatg cgtcattttccacaaatctt gtgtgcagtg tagattataa 1680 tcacatccag ccagtgtggc aacttctggctttatacagt gactctcctc tgatactaga 1740 aaggaagccc cagcttaccg agactccttcactgtcttct agatataaac aggtggctct 1800 taggcctgaa gacattttta ccagcatagaggctgatgtc agagcagacc ctttttggtt 1860 ccaacaagaa aaaattgtct tgcagctgaacagaactgcc accacactta gcacattaca 1920 gatccagttt tccactgatg ctcaaatcgctttaccaagg gcggagatga gagcggagag 1980 actcaaatgg accatgatcc tgatgatgaacaatcccaaa ctggaacgca ctgtcctggt 2040 tggcggcact attgccctga gctgtccaggcaaaggcgac ccttcacctc acttggaatg 2100 gcttctagct gatgggagta aagtgagagccccttacgtt agcgaggatg ggcgaatcct 2160 aatagacaaa aatgggaagt tggaactgcagatggctgac agctttgatg caggtcttta 2220 ccactgcata agcaccaatg atgcagatgcggatgttctc acatacagga taactgtggt 2280 agagccctat ggagaaagca cacatgacagtggagtccag cacacagtgg ttacgggtga 2340 gacgctcgac cttccatgcc tttccacgggtgttccagat gcttctatta gctggattct 2400 tccagggaac actgtgttct ctcagccatcaagagacagg caaattctta acaatgggac 2460 cttaagaata ttacaggtta cgccaaaagatcaaggtcat taccaatgtg tggctgccaa 2520 cccatcaggg gccgactttt ccagttttaaagtttcagtt caaaagaaag gccaaaggat 2580 ggttgagcat gacagggagg caggtggatctggacttgga gaacccaact ccagtgtttc 2640 ccttaagcag ccagcatctt tgaaactctctgcatcagct ttgacagggt cagaggctgg 2700 aaaacaagtc tccggtgtac ataggaagaacaaacataga gacttaatac atcggcggcg 2760 tggggattcc acgctccggc gattcagggagcataggagg cagctccctc tctctgctcg 2820 gagaattgac ccgcaacgct gggcagcacttctagaaaaa gccaaaaaga attctgtgcc 2880 aaaaaagcaa gaaaatacca cagtaaagccagtgccactg gctgttcccc tcgtggaact 2940 cactgacgag gaaaaggatg cctctggcatgattcctcca gatgaagaat tcatggttct 3000 gaaaactaag gcttctggtg tcccaggaaggtcaccaact gctgactctg gaccagtaaa 3060 tcatggtttt atgacgagta tagcttctggcacagaagtc tcaactgtga atccacaaac 3120 actacaatct gagcaccttc ctgatttcaaattatttagt gtaacaaacg gtacagctgt 3180 gacaaagagt atgaacccat ccatagcaagcaaaatagaa gatacaacca accaaaaccc 3240 aatcattatc tttccatcag tagctgaaattcgagattct gctcaggcag gaagagcatc 3300 ttcccaaagt gcacaccctg taacagggggaaacatggct acctatggcc ataccaacac 3360 atatagtagc tttaccagca aagccagtacagtcttgcag ccaataaatc caacagaaag 3420 ttatggacct cagataccta ttacaggagtcagcagacct agcagtagtg acatctcttc 3480 tcacactact gcagacccta gcttctccagtcacccttca ggttcacaca ccactgcctc 3540 gtctttattt cacattccta gaaacaacaatacaggtaac ttccccttgt ccaggcactt 3600 gggaagagag aggacaattt ggagcagagggagagttaaa aacccacata gaaccccagt 3660 tctccgacgg catagacaca ggactgtgaggccagcaatc aagggacctg ctaacaaaaa 3720 tgtgagccaa gttccagcca cagagtaccctgggatgtgc cacacatgtc cttccgcaga 3780 ggggctcaca gtggctactg cagcactgtcagttccaagt tcatcccaca gtgccctccc 3840 caaaactaat aatgttgggg tcatagcagaagagtctacc actgtggtca agaaaccact 3900 gttactattt aaggacaaac aaaatgtagatattgagata ataacaacca ctacaaaata 3960 ttccggaggg gaaagtaacc acgtgattcctacggaagca agcatgactt ctgctccaac 4020 atctgtatcc ctggggaaat ctcctgtagacaatagtggt cacctgagca tgcctgggac 4080 catccaaact gggaaagatt cagtggaaacaacaccactt cccagccccc tcagcacacc 4140 ctcaatacca acaagcacaa aattctcaaagaggaaaact cccttgcacc agatctttgt 4200 aaataaccag aagaaggagg ggatgttaaagaatccatat caattcggtt tacaaaagaa 4260 cccagccgca aagcttccca aaatagctcctcttttaccc acaggtcaga gttccccctc 4320 agattctaca actctcttga caagtccgccaccagctctg tctacaacaa tggctgccac 4380 tcagaacaag ggcactgaag tagtatcaggtgccagaagt ctctcagcag ggaagaagca 4440 gcccttcacc aactcctctc cagtgcttcctagcaccata agcaagagat ctaatacatt 4500 aaacttcttg tcaacggaaa cccccacagtgacaagtcct actgctactg catctgtcat 4560 tatgtctgaa acccaacgaa caagatccaaagaagcaaaa gaccaaataa aggggcctcg 4620 gaagaacaga aacaacgcaa acaccacccccaggcaggtt tctggctata gtgcatactc 4680 agctctaaca acagctgata cccccttggctttcagtcat tccccacgac aagatgatgg 4740 tggaaatgta agtgcagttg cttatcactcaacaacctct cttctggcca taactgaact 4800 gtttgagaag tacacccaga ctttgggaaatacaacagct ttggaaacaa cgttgttgag 4860 caaatcacag gagagtacca cagtgaaaagagcctcagac acaccaccac cactcctcag 4920 cagtggggcg cccccagtgc ccactccttccccacctcct tttactaagg gtgtggttac 4980 agacagcaaa gtcacatcag ctttccagatgacgtcaaat agagtggtca ccatatatga 5040 atcttcaagg cacaatacag atctgcagcaaccctcagca gaggctagcc ccaatcctga 5100 gatcataact ggaaccactg actctccctctaatctgttt ccatccactt ctgtgccagc 5160 actaagggta gataaaccac agaattctaaatggaagccc tctccctggc cagaacacaa 5220 atatcagctc aagtcatact ccgaaaccattgagaagggc aaaaggccag cagtaagcat 5280 gtccccccac ctcagccttc cagaggccagcactcatgcc tcacactgga atacacagaa 5340 gcatgcagaa aagagtgttt ttgataagaaacctggtcaa aacccaactt ccaaacatct 5400 gccttacgtc tctctaccta agactctattgaaaaagcca agaataattg gaggaaaggc 5460 tgcaagcttt acagttccag ctaattcagacgtttttctt ccttgtgagg ctgttggaga 5520 cccactgccc atcatccact ggaccagagtttcatcagga nttgaaatat cccaagggac 5580 acagaaaagc cggttccacg tgcttcccaatggcaccttg tccatccaga gggtcagtat 5640 tcaggaccgt ggacagtacc tgtgctctgcatttaatcca ctgggcgtag accattttca 5700 tgtctctttg tctgtggttt tttacccggcaaggattttg gacagacatg tcaaggagat 5760 cacagttcac tttggaagta ctgtggaactaaagtgcaga gtggagggta tgccgaggcc 5820 tacggtttcc tggatacttg caaaccaaacggtggtctca gaaacggcca agggaagcag 5880 aaaggtctgg gtaacacctg atggaacattgatcatctat aatctgagtc tttatgatcg 5940 tggtttttac aagtgtgtgg ccagcaacccatctggccag gattcactgt tggttaagat 6000 acaagtcatc acagctcccc ctgtcattatagagcaaaag aggcaagcca tcgttggggt 6060 tttaggtgga agtttgaaac tgccctgcactgcaaaagga actccccagc ctagtgttca 6120 ctgggtcctt tatgatggga ctgaactaaaaccattgcag ttgactcatt ccagattttt 6180 cttgtatcca aatggaactc tgtatataagaagcatcgct ccttcagtga ggggcactta 6240 tgagtgcatt gccaccagct cctcaggctcagagagaagg gtagtgattc ttactgtgga 6300 agagggagag acaatcccca ggatagaaactgcctctcag aaatggactg aggtgaattt 6360 gggtgagaaa ttactactga actgctcagctactggggat ccaaagccta gaataatctg 6420 gaggctgcca tccaaggctg tcatcgaccagtggcacaga atgggcagcc gaatccacgt 6480 ctacccaaat ggatccttgg tggttgggtcagtgacggaa aaagacgctg gtgactactt 6540 atgtgtggca agaaacaaaa tgggagatgacctagtcctg atgcatgtcc gcctgagatt 6600 gacacctgcc aaaattgaac agaagcagtattttaagaag caagtgctcc atgggaaaga 6660 tttccaagtt gactgcaagg cctctggctcccctgtgcct gaggtatcct ggagtttgcc 6720 tgatgggaca gtgctcaaca atgtagcccaagctgatgac agtggctata ggaccaagag 6780 gtacaccctt ttccacaatg gaaccttgtatttcaacaac gttgggatgg cagaggaagg 6840 agattatatc tgctctgccc agaacaccttagggaaagat gagatgaaag tccacctaac 6900 agttctaaca gccatcccac ggataaggcaaagctacaag accaccatga ggctcagggc 6960 tggagaaaca gctgtccttg actgcgaggtcactggggaa ccgaagccca atgtattttg 7020 gttgctgcct tccaacaatg tcatttcattctccaatgac aggttcacat ttcatgccaa 7080 tagaactttg tccatccata aagtgaaaccacttgactct ggggactatg tgtgcgtagc 7140 tcagaatcct agtggggatg acactaagacatacaaactg gacattgtct ctaaacctcc 7200 attaatcaat ggcctgtatg caaacaagactgttattaaa gccacagcca ttcggcactc 7260 caaaaaatac tttgactgca gagcagatgggatcccatct tcccaggtca cgtggattat 7320 gccaggcaat attttcctcc cagctccatactttggaagc agagtcacgg tccatccaaa 7380 tggaaccttg gagatgagga acatccggctttctgactct gcggacttca cctgtgtggt 7440 tcggagcgag ggaggagaga gtgtgttggtagtgcagtta gaagtcctag aaatgctgag 7500 aagaccaaca ttcagaaacc cattcaacgaaaaagtcatc gcccaagctg gcaagcccgt 7560 agcactgaac tgctctgtgg atgggaaccccccacctgaa attacctgga tcttacctga 7620 cggcacacag tttgctaaca gaccacacaattccccgtat ctgatggcag gcaatggctc 7680 tctcatcctt tacaaagcaa ctcggaacaagtcagggaag tatcgctgtg cagccaggaa 7740 taaggttggc tacatcgaga aactcatcctgttagagatt gggcagaagc cagtcattct 7800 gacatacgaa ccagggatgg tgaagagcgtcagtggggaa ccgttatcac tgcattgtgt 7860 gtctgatggg atccccaagc caaatgtcaagtggactaca ccgggtggcc atgtaatcga 7920 caggcctcaa gtggatggaa aatacatactgcatgaaaat ggcacgctgg tcatcaaagc 7980 aacaacagct cacgaccaag gaaattatatctgtagggct caaaacagtg ttggccaggc 8040 agttattagc gtgtcagtga tggttgtggcctaccctccc cgaatcataa actacctacc 8100 caggaacatg ctcaggagga caggggaagccatgcagctc cactgtgtgg ccttgggaat 8160 ccccaagcca aaagtcacct gggagacgccaagacactcc ctgctctcaa aagcaacagc 8220 aagaaaaccc catagaagtg agatgcttcacccacaaggt acgctggtca ttcagaatct 8280 ccaaacctcg gattccggag tctataagtgcagagctcag aacctacttg ggactgatta 8340 cgcaacaact tacatccagg tactctgacaggaaggggga gactaaaatt caacagaagt 8400 ccacatccac agggtttatt ttttggaagaagtttaatca aaggcagcca taggcatgta 8460 aatgagtctg aatacattta cagtattaaatttacaatgg acatgcgatg agacttgtaa 8520 atgaaagcat tgtgaactga aaccgagtctctgtggatct caaagcaaac tcttaactta 8580 aggcactttg attttgccaa caaataataacaaacattaa gagaaaaaaa tgatccacta 8640 cgaaataaca aacggctaat gcacctgaattctcagtaaa aagacctttc tctcgctaac 8700 agttgccagc tgcctcgtgt ctgtttcctaccaatgtcac aaacatcgca cacagggtga 8760 atggagtcaa cgggaaagat taagtttgcggtctgtgtaa atctcaatgt acaaatattc 8820 tgtcnctggt ttataaacat tttgataaaaccgaaaaaaa aaaaaaaaaa aaaaaaaaaa 8880 aaa 8883 2 2597 PRT rattus speciesmisc_feature (1)..(2597) ′x′ can be any amino acid 2 Met Gln Val Arg GlyArg Glu Val Ser Gly Leu Leu Ile Ser Leu Thr 1 5 10 15 Ala Val Cys LeuVal Val Thr Pro Gly Ser Arg Ala Cys Pro Arg Arg 20 25 30 Cys Ala Cys TyrVal Pro Thr Glu Val His Cys Thr Phe Arg Tyr Leu 35 40 45 Thr Ser Ile ProAsp Gly Ile Pro Ala Asn Val Glu Arg Ile Asn Leu 50 55 60 Gly Tyr Asn SerLeu Thr Arg Leu Thr Glu Asn Asp Phe Asp Gly Leu 65 70 75 80 Ser Lys LeuGlu Leu Leu Met Leu His Ser Asn Gly Ile His Arg Val 85 90 95 Ser Asp LysThr Phe Ser Gly Leu Gln Ser Leu Gln Val Leu Lys Met 100 105 110 Ser TyrAsn Lys Val Gln Ile Ile Arg Lys Asp Thr Phe Tyr Gly Leu 115 120 125 GlySer Leu Val Arg Leu His Leu Asp His Asn Asn Ile Glu Phe Ile 130 135 140Asn Pro Glu Ala Phe Tyr Gly Leu Thr Ser Leu Arg Leu Val His Leu 145 150155 160 Glu Gly Asn Arg Leu Thr Lys Leu His Pro Asp Thr Phe Val Ser Leu165 170 175 Ser Tyr Leu Gln Ile Phe Lys Thr Ser Phe Ile Lys Tyr Leu PheLeu 180 185 190 Ser Asp Asn Phe Leu Thr Ser Leu Pro Lys Glu Met Val SerTyr Met 195 200 205 Pro Asn Leu Glu Ser Leu Tyr Leu His Gly Asn Pro TrpThr Cys Asp 210 215 220 Cys His Leu Lys Trp Leu Ser Glu Trp Met Gln GlyAsn Pro Asp Ile 225 230 235 240 Ile Lys Cys Lys Lys Asp Arg Ser Ser SerSer Pro Gln Gln Cys Pro 245 250 255 Leu Cys Met Asn Pro Arg Ile Ser LysGly Arg Pro Phe Ala Met Val 260 265 270 Pro Ser Gly Ala Phe Leu Cys ThrLys Pro Thr Ile Asp Pro Ser Leu 275 280 285 Lys Ser Lys Ser Leu Val ThrGln Glu Asp Asn Gly Ser Ala Ser Thr 290 295 300 Ser Pro Gln Asp Phe IleGlu Pro Phe Gly Ser Leu Ser Leu Asn Met 305 310 315 320 Thr Xaa Xaa SerGly Asn Lys Ala Asp Met Val Cys Ser Ile Gln Lys 325 330 335 Pro Ser ArgThr Ser Pro Thr Ala Phe Thr Glu Glu Asn Asp Tyr Ile 340 345 350 Met LeuAsn Ala Ser Phe Ser Thr Asn Leu Val Cys Ser Val Asp Tyr 355 360 365 AsnHis Ile Gln Pro Val Trp Gln Leu Leu Ala Leu Tyr Ser Asp Ser 370 375 380Pro Leu Ile Leu Glu Arg Lys Pro Gln Leu Thr Glu Thr Pro Ser Leu 385 390395 400 Ser Ser Arg Tyr Lys Gln Val Ala Leu Arg Pro Glu Asp Ile Phe Thr405 410 415 Ser Ile Glu Ala Asp Val Arg Ala Asp Pro Phe Trp Phe Gln GlnGlu 420 425 430 Lys Ile Val Leu Gln Leu Asn Arg Thr Ala Thr Thr Leu SerThr Leu 435 440 445 Gln Ile Gln Phe Ser Thr Asp Ala Gln Ile Ala Leu ProArg Ala Glu 450 455 460 Met Arg Ala Glu Arg Leu Lys Trp Thr Met Ile LeuMet Met Asn Asn 465 470 475 480 Pro Lys Leu Glu Arg Thr Val Leu Val GlyGly Thr Ile Ala Leu Ser 485 490 495 Cys Pro Gly Lys Gly Asp Pro Ser ProHis Leu Glu Trp Leu Leu Ala 500 505 510 Asp Gly Ser Lys Val Arg Ala ProTyr Val Ser Glu Asp Gly Arg Ile 515 520 525 Leu Ile Asp Lys Asn Gly LysLeu Glu Leu Gln Met Ala Asp Ser Phe 530 535 540 Asp Ala Gly Leu Tyr HisCys Ile Ser Thr Asn Asp Ala Asp Ala Asp 545 550 555 560 Val Leu Thr TyrArg Ile Thr Val Val Glu Pro Tyr Gly Glu Ser Thr 565 570 575 His Asp SerGly Val Gln His Thr Val Val Thr Gly Glu Thr Leu Asp 580 585 590 Leu ProCys Leu Ser Thr Gly Val Pro Asp Ala Ser Ile Ser Trp Ile 595 600 605 LeuPro Gly Asn Thr Val Phe Ser Gln Pro Ser Arg Asp Arg Gln Ile 610 615 620Leu Asn Asn Gly Thr Leu Arg Ile Leu Gln Val Thr Pro Lys Asp Gln 625 630635 640 Gly His Tyr Gln Cys Val Ala Ala Asn Pro Ser Gly Ala Asp Phe Ser645 650 655 Ser Phe Lys Val Ser Val Gln Lys Lys Gly Gln Arg Met Val GluHis 660 665 670 Asp Arg Glu Ala Gly Gly Ser Gly Leu Gly Glu Pro Asn SerSer Val 675 680 685 Ser Leu Lys Gln Pro Ala Ser Leu Lys Leu Ser Ala SerAla Leu Thr 690 695 700 Gly Ser Glu Ala Gly Lys Gln Val Ser Gly Val HisArg Lys Asn Lys 705 710 715 720 His Arg Asp Leu Ile His Arg Arg Arg GlyAsp Ser Thr Leu Arg Arg 725 730 735 Phe Arg Glu His Arg Arg Gln Leu ProLeu Ser Ala Arg Arg Ile Asp 740 745 750 Pro Gln Arg Trp Ala Ala Leu LeuGlu Lys Ala Lys Lys Asn Ser Val 755 760 765 Pro Lys Lys Gln Glu Asn ThrThr Val Lys Pro Val Pro Leu Ala Val 770 775 780 Pro Leu Val Glu Leu ThrAsp Glu Glu Lys Asp Ala Ser Gly Met Ile 785 790 795 800 Pro Pro Asp GluGlu Phe Met Val Leu Lys Thr Lys Ala Ser Gly Val 805 810 815 Pro Gly ArgSer Pro Thr Ala Asp Ser Gly Pro Val Asn His Gly Phe 820 825 830 Met ThrSer Ile Ala Ser Gly Thr Glu Val Ser Thr Val Asn Pro Gln 835 840 845 ThrLeu Gln Ser Glu His Leu Pro Asp Phe Lys Leu Phe Ser Val Thr 850 855 860Asn Gly Thr Ala Val Thr Lys Ser Met Asn Pro Ser Ile Ala Ser Lys 865 870875 880 Ile Glu Asp Thr Thr Asn Gln Asn Pro Ile Ile Ile Phe Pro Ser Val885 890 895 Ala Glu Ile Arg Asp Ser Ala Gln Ala Gly Arg Ala Ser Ser GlnSer 900 905 910 Ala His Pro Val Thr Gly Gly Asn Met Ala Thr Tyr Gly HisThr Asn 915 920 925 Thr Tyr Ser Ser Phe Thr Ser Lys Ala Ser Thr Val LeuGln Pro Ile 930 935 940 Asn Pro Thr Glu Ser Tyr Gly Pro Gln Ile Pro IleThr Gly Val Ser 945 950 955 960 Arg Pro Ser Ser Ser Asp Ile Ser Ser HisThr Thr Ala Asp Pro Ser 965 970 975 Phe Ser Ser His Pro Ser Gly Ser HisThr Thr Ala Ser Ser Leu Phe 980 985 990 His Ile Pro Arg Asn Asn Asn ThrGly Asn Phe Pro Leu Ser Arg His 995 1000 1005 Leu Gly Arg Glu Arg ThrIle Trp Ser Arg Gly Arg Val Lys Asn 1010 1015 1020 Pro His Arg Thr ProVal Leu Arg Arg His Arg His Arg Thr Val 1025 1030 1035 Arg Pro Ala IleLys Gly Pro Ala Asn Lys Asn Val Ser Gln Val 1040 1045 1050 Pro Ala ThrGlu Tyr Pro Gly Met Cys His Thr Cys Pro Ser Ala 1055 1060 1065 Glu GlyLeu Thr Val Ala Thr Ala Ala Leu Ser Val Pro Ser Ser 1070 1075 1080 SerHis Ser Ala Leu Pro Lys Thr Asn Asn Val Gly Val Ile Ala 1085 1090 1095Glu Glu Ser Thr Thr Val Val Lys Lys Pro Leu Leu Leu Phe Lys 1100 11051110 Asp Lys Gln Asn Val Asp Ile Glu Ile Ile Thr Thr Thr Thr Lys 11151120 1125 Tyr Ser Gly Gly Glu Ser Asn His Val Ile Pro Thr Glu Ala Ser1130 1135 1140 Met Thr Ser Ala Pro Thr Ser Val Ser Leu Gly Lys Ser ProVal 1145 1150 1155 Asp Asn Ser Gly His Leu Ser Met Pro Gly Thr Ile GlnThr Gly 1160 1165 1170 Lys Asp Ser Val Glu Thr Thr Pro Leu Pro Ser ProLeu Ser Thr 1175 1180 1185 Pro Ser Ile Pro Thr Ser Thr Lys Phe Ser LysArg Lys Thr Pro 1190 1195 1200 Leu His Gln Ile Phe Val Asn Asn Gln LysLys Glu Gly Met Leu 1205 1210 1215 Lys Asn Pro Tyr Gln Phe Gly Leu GlnLys Asn Pro Ala Ala Lys 1220 1225 1230 Leu Pro Lys Ile Ala Pro Leu LeuPro Thr Gly Gln Ser Ser Pro 1235 1240 1245 Ser Asp Ser Thr Thr Leu LeuThr Ser Pro Pro Pro Ala Leu Ser 1250 1255 1260 Thr Thr Met Ala Ala ThrGln Asn Lys Gly Thr Glu Val Val Ser 1265 1270 1275 Gly Ala Arg Ser LeuSer Ala Gly Lys Lys Gln Pro Phe Thr Asn 1280 1285 1290 Ser Ser Pro ValLeu Pro Ser Thr Ile Ser Lys Arg Ser Asn Thr 1295 1300 1305 Leu Asn PheLeu Ser Thr Glu Thr Pro Thr Val Thr Ser Pro Thr 1310 1315 1320 Ala ThrAla Ser Val Ile Met Ser Glu Thr Gln Arg Thr Arg Ser 1325 1330 1335 LysGlu Ala Lys Asp Gln Ile Lys Gly Pro Arg Lys Asn Arg Asn 1340 1345 1350Asn Ala Asn Thr Thr Pro Arg Gln Val Ser Gly Tyr Ser Ala Tyr 1355 13601365 Ser Ala Leu Thr Thr Ala Asp Thr Pro Leu Ala Phe Ser His Ser 13701375 1380 Pro Arg Gln Asp Asp Gly Gly Asn Val Ser Ala Val Ala Tyr His1385 1390 1395 Ser Thr Thr Ser Leu Leu Ala Ile Thr Glu Leu Phe Glu LysTyr 1400 1405 1410 Thr Gln Thr Leu Gly Asn Thr Thr Ala Leu Glu Thr ThrLeu Leu 1415 1420 1425 Ser Lys Ser Gln Glu Ser Thr Thr Val Lys Arg AlaSer Asp Thr 1430 1435 1440 Pro Pro Pro Leu Leu Ser Ser Gly Ala Pro ProVal Pro Thr Pro 1445 1450 1455 Ser Pro Pro Pro Phe Thr Lys Gly Val ValThr Asp Ser Lys Val 1460 1465 1470 Thr Ser Ala Phe Gln Met Thr Ser AsnArg Val Val Thr Ile Tyr 1475 1480 1485 Glu Ser Ser Arg His Asn Thr AspLeu Gln Gln Pro Ser Ala Glu 1490 1495 1500 Ala Ser Pro Asn Pro Glu IleIle Thr Gly Thr Thr Asp Ser Pro 1505 1510 1515 Ser Asn Leu Phe Pro SerThr Ser Val Pro Ala Leu Arg Val Asp 1520 1525 1530 Lys Pro Gln Asn SerLys Trp Lys Pro Ser Pro Trp Pro Glu His 1535 1540 1545 Lys Tyr Gln LeuLys Ser Tyr Ser Glu Thr Ile Glu Lys Gly Lys 1550 1555 1560 Arg Pro AlaVal Ser Met Ser Pro His Leu Ser Leu Pro Glu Ala 1565 1570 1575 Ser ThrHis Ala Ser His Trp Asn Thr Gln Lys His Ala Glu Lys 1580 1585 1590 SerVal Phe Asp Lys Lys Pro Gly Gln Asn Pro Thr Ser Lys His 1595 1600 1605Leu Pro Tyr Val Ser Leu Pro Lys Thr Leu Leu Lys Lys Pro Arg 1610 16151620 Ile Ile Gly Gly Lys Ala Ala Ser Phe Thr Val Pro Ala Asn Ser 16251630 1635 Asp Val Phe Leu Pro Cys Glu Ala Val Gly Asp Pro Leu Pro Ile1640 1645 1650 Ile His Trp Thr Arg Val Ser Ser Gly Xaa Glu Ile Ser GlnGly 1655 1660 1665 Thr Gln Lys Ser Arg Phe His Val Leu Pro Asn Gly ThrLeu Ser 1670 1675 1680 Ile Gln Arg Val Ser Ile Gln Asp Arg Gly Gln TyrLeu Cys Ser 1685 1690 1695 Ala Phe Asn Pro Leu Gly Val Asp His Phe HisVal Ser Leu Ser 1700 1705 1710 Val Val Phe Tyr Pro Ala Arg Ile Leu AspArg His Val Lys Glu 1715 1720 1725 Ile Thr Val His Phe Gly Ser Thr ValGlu Leu Lys Cys Arg Val 1730 1735 1740 Glu Gly Met Pro Arg Pro Thr ValSer Trp Ile Leu Ala Asn Gln 1745 1750 1755 Thr Val Val Ser Glu Thr AlaLys Gly Ser Arg Lys Val Trp Val 1760 1765 1770 Thr Pro Asp Gly Thr LeuIle Ile Tyr Asn Leu Ser Leu Tyr Asp 1775 1780 1785 Arg Gly Phe Tyr LysCys Val Ala Ser Asn Pro Ser Gly Gln Asp 1790 1795 1800 Ser Leu Leu ValLys Ile Gln Val Ile Thr Ala Pro Pro Val Ile 1805 1810 1815 Ile Glu GlnLys Arg Gln Ala Ile Val Gly Val Leu Gly Gly Ser 1820 1825 1830 Leu LysLeu Pro Cys Thr Ala Lys Gly Thr Pro Gln Pro Ser Val 1835 1840 1845 HisTrp Val Leu Tyr Asp Gly Thr Glu Leu Lys Pro Leu Gln Leu 1850 1855 1860Thr His Ser Arg Phe Phe Leu Tyr Pro Asn Gly Thr Leu Tyr Ile 1865 18701875 Arg Ser Ile Ala Pro Ser Val Arg Gly Thr Tyr Glu Cys Ile Ala 18801885 1890 Thr Ser Ser Ser Gly Ser Glu Arg Arg Val Val Ile Leu Thr Val1895 1900 1905 Glu Glu Gly Glu Thr Ile Pro Arg Ile Glu Thr Ala Ser GlnLys 1910 1915 1920 Trp Thr Glu Val Asn Leu Gly Glu Lys Leu Leu Leu AsnCys Ser 1925 1930 1935 Ala Thr Gly Asp Pro Lys Pro Arg Ile Ile Trp ArgLeu Pro Ser 1940 1945 1950 Lys Ala Val Ile Asp Gln Trp His Arg Met GlySer Arg Ile His 1955 1960 1965 Val Tyr Pro Asn Gly Ser Leu Val Val GlySer Val Thr Glu Lys 1970 1975 1980 Asp Ala Gly Asp Tyr Leu Cys Val AlaArg Asn Lys Met Gly Asp 1985 1990 1995 Asp Leu Val Leu Met His Val ArgLeu Arg Leu Thr Pro Ala Lys 2000 2005 2010 Ile Glu Gln Lys Gln Tyr PheLys Lys Gln Val Leu His Gly Lys 2015 2020 2025 Asp Phe Gln Val Asp CysLys Ala Ser Gly Ser Pro Val Pro Glu 2030 2035 2040 Val Ser Trp Ser LeuPro Asp Gly Thr Val Leu Asn Asn Val Ala 2045 2050 2055 Gln Ala Asp AspSer Gly Tyr Arg Thr Lys Arg Tyr Thr Leu Phe 2060 2065 2070 His Asn GlyThr Leu Tyr Phe Asn Asn Val Gly Met Ala Glu Glu 2075 2080 2085 Gly AspTyr Ile Cys Ser Ala Gln Asn Thr Leu Gly Lys Asp Glu 2090 2095 2100 MetLys Val His Leu Thr Val Leu Thr Ala Ile Pro Arg Ile Arg 2105 2110 2115Gln Ser Tyr Lys Thr Thr Met Arg Leu Arg Ala Gly Glu Thr Ala 2120 21252130 Val Leu Asp Cys Glu Val Thr Gly Glu Pro Lys Pro Asn Val Phe 21352140 2145 Trp Leu Leu Pro Ser Asn Asn Val Ile Ser Phe Ser Asn Asp Arg2150 2155 2160 Phe Thr Phe His Ala Asn Arg Thr Leu Ser Ile His Lys ValLys 2165 2170 2175 Pro Leu Asp Ser Gly Asp Tyr Val Cys Val Ala Gln AsnPro Ser 2180 2185 2190 Gly Asp Asp Thr Lys Thr Tyr Lys Leu Asp Ile ValSer Lys Pro 2195 2200 2205 Pro Leu Ile Asn Gly Leu Tyr Ala Asn Lys ThrVal Ile Lys Ala 2210 2215 2220 Thr Ala Ile Arg His Ser Lys Lys Tyr PheAsp Cys Arg Ala Asp 2225 2230 2235 Gly Ile Pro Ser Ser Gln Val Thr TrpIle Met Pro Gly Asn Ile 2240 2245 2250 Phe Leu Pro Ala Pro Tyr Phe GlySer Arg Val Thr Val His Pro 2255 2260 2265 Asn Gly Thr Leu Glu Met ArgAsn Ile Arg Leu Ser Asp Ser Ala 2270 2275 2280 Asp Phe Thr Cys Val ValArg Ser Glu Gly Gly Glu Ser Val Leu 2285 2290 2295 Val Val Gln Leu GluVal Leu Glu Met Leu Arg Arg Pro Thr Phe 2300 2305 2310 Arg Asn Pro PheAsn Glu Lys Val Ile Ala Gln Ala Gly Lys Pro 2315 2320 2325 Val Ala LeuAsn Cys Ser Val Asp Gly Asn Pro Pro Pro Glu Ile 2330 2335 2340 Thr TrpIle Leu Pro Asp Gly Thr Gln Phe Ala Asn Arg Pro His 2345 2350 2355 AsnSer Pro Tyr Leu Met Ala Gly Asn Gly Ser Leu Ile Leu Tyr 2360 2365 2370Lys Ala Thr Arg Asn Lys Ser Gly Lys Tyr Arg Cys Ala Ala Arg 2375 23802385 Asn Lys Val Gly Tyr Ile Glu Lys Leu Ile Leu Leu Glu Ile Gly 23902395 2400 Gln Lys Pro Val Ile Leu Thr Tyr Glu Pro Gly Met Val Lys Ser2405 2410 2415 Val Ser Gly Glu Pro Leu Ser Leu His Cys Val Ser Asp GlyIle 2420 2425 2430 Pro Lys Pro Asn Val Lys Trp Thr Thr Pro Gly Gly HisVal Ile 2435 2440 2445 Asp Arg Pro Gln Val Asp Gly Lys Tyr Ile Leu HisGlu Asn Gly 2450 2455 2460 Thr Leu Val Ile Lys Ala Thr Thr Ala His AspGln Gly Asn Tyr 2465 2470 2475 Ile Cys Arg Ala Gln Asn Ser Val Gly GlnAla Val Ile Ser Val 2480 2485 2490 Ser Val Met Val Val Ala Tyr Pro ProArg Ile Ile Asn Tyr Leu 2495 2500 2505 Pro Arg Asn Met Leu Arg Arg ThrGly Glu Ala Met Gln Leu His 2510 2515 2520 Cys Val Ala Leu Gly Ile ProLys Pro Lys Val Thr Trp Glu Thr 2525 2530 2535 Pro Arg His Ser Leu LeuSer Lys Ala Thr Ala Arg Lys Pro His 2540 2545 2550 Arg Ser Glu Met LeuHis Pro Gln Gly Thr Leu Val Ile Gln Asn 2555 2560 2565 Leu Gln Thr SerAsp Ser Gly Val Tyr Lys Cys Arg Ala Gln Asn 2570 2575 2580 Leu Leu GlyThr Asp Tyr Ala Thr Thr Tyr Ile Gln Val Leu 2585 2590 2595 3 11967 DNAmouse sp misc_feature (1)..(11967) ′n′ can be any nucleotide ′a′, ′c′,′g′ or ′t′. 3 tttggaacca acccagatgc ccctcaacag agaaatgggc cagaaaatgtggtccattta 60 tccaatggaa tactactcaa cttattaaaa acaacgactt tcataaaatttttaggcaaa 120 tgnatggtct gnaggatctt gagtgaggta acccaatcac aaaagaacactcatggtatg 180 cactcactga taagtggcta tttgtctatg gagtgattta aaagggaagaagacacatag 240 ctttttgtgt gtataatatt aagatggaaa tttgccagtg ctgtttggcttatgagtgaa 300 tcttgtttca gtggattacc ggaagaaaat aataagtgaa ctgtaggaagaagtagttaa 360 tcaaggtgac aaagtatcct gacacattgg gaaaagacca cagtccaggaaactgagtct 420 taaggattca tattaactcc agttccccat gtgcagctct gagactttggcagatcagac 480 acttaacttc accagcttcc tacacagagc agttactatc cttgcacttcacacatggag 540 tgtgaccatt aagctgcact gaaacatgag tctgacttgt taataatcttaaaatacaaa 600 ttgtgttgta aagtatgtga ccaaagagca tggtcatgct attaacctttgatgttctat 660 ggactcttaa ttttatggta gaaatgtcaa caagcttgtg gaggctggaagatacaaggc 720 ttaagaggat ggcctttcag ttttgaaagt aattcagtat gtgttctggcatcccttttc 780 ctaaagcaat ttaacccccc aagtaggcat aattttaatg cttacttcatcagaatatgt 840 ctaattgact cttctaaaaa gactttggta tgcataggat ctaaatgtaaatgtgattta 900 ctgacataat aaataggaga aactgagcta gaataggtat aaaatatgtgctggctttct 960 aataggtctt ataggttata taagaggtgg gaaaggaata tttgaaacatctagaagtaa 1020 aatgatcctg agtagcgatc ctgggaaaat acgtactcta acacactgcaatcatctctc 1080 tgtggtttgc tggagctgag gtctggaagg ctcgaccttg gttagaaataacctaccgaa 1140 tacagagcta tgacgttagt ctggaaggag ctttggaaga atgacaagctgtagctgccc 1200 agaacatact agatgccata tttccaaggc aagtgtccac atgcggacatcttaagaata 1260 tggttgtctc tgcagtgcta aggaccttgt tcgtgccaca caggtctccagggttagtgc 1320 taactctgac tgcttgactc tttaattcta ccttgatcat taatgactagaaatcacttg 1380 gtgattagca actggatatg gaatattact aatttgtacc caagccaggccacctcagct 1440 ttggcagctc cattcattct gtggagccca gtcacgtggg tttgaatcaactgtactgtt 1500 tctacttaca agacgcatta cctgagatga gtcatttttc ttcacaagtctttttagaag 1560 agtcaattag acatattctg atgaagtaag catataaagt gagagcagcatgaatgtgtt 1620 ccatgtatgc tcatggatgc tattataatg tggaaataaa ctgactttaaaaaaaaaagc 1680 ttatgatact tgtcacagag taaatcttcc ataaatatca tctgcatttataaattattt 1740 tcataatcca tcaattaaaa acctttagaa attttgttaa cacaaagatccctaggcccc 1800 tgccctagga tggtctgtat ggtgggcctg agagatggag cttaagaacttacttgctcc 1860 aggagcacat cttcagaaca tctgcctcaa aacatttatc ccaaatgctcatcaaaggct 1920 cactcacatg tgcttcaacc acagggatta aacagtcatt ttagtcacatttctcaaacg 1980 gtggaagcct gctagaggaa caggatgtat caggataaca tccaaccttacaaaaggatg 2040 tcataaccct caccacaaca aacaacaacg acaacaaacc cataaaaattatcacggcaa 2100 atgaactaag ccatatgcag aaaaagtatt atatgttctc attgtggggtgtttttcctt 2160 aatagtcaaa tatgcagaat atagacaaag atggtttatg caagtggggatggcgaagga 2220 tacttgtaga ttagaggaca caaagcaaca actacagagt gaagtaatccagagacttaa 2280 tgtataatat gaggactgta tttaataatt ctatttaaga tacacagcaaacgagtgtat 2340 cttactaaca cacacactta catagagaga ataaagtgat agatacgtttgttttatctt 2400 catgtagctg ataatttcat attgtacacc tcaaacatag ataaccaacaaagaggaaga 2460 ggataggtgc ctctcccagg gcggaagagt acattcgaaa gtcagacaccattgtgtaga 2520 tgtaccacat ggaggagcta gagaaagtag ccaaggagct aaagggatctgcaaccctat 2580 aggtggaaca acattatgag ctaaccagta ccccggagct cttgactctagctgcatata 2640 tatcaaaaga tggcctaatc ggccatcact ggaaagagag gcccattggacttgcaaact 2700 ttatatgccc cagtacaggg gaataccagg gccaaaaagg gggagtgggtgggcagggga 2760 gtgggggtgg gtggatatgg gggacttttg gtatagcatt ggaaatgtaaatgagttaaa 2820 tacctaataa aaaatggaaa aaaaaaaaaa aaaaaaaaaa aaggaaggtcagacacctca 2880 cttcactgct atctcaactt gcaaacagaa ggggagtcac aaacccaggacaaaccacag 2940 tgattgaagc gtctttgaat gttattgctg ttgttgttac caccatcattagcatatatt 3000 cattgtgaaa acttacgggg tctatgacat gtttttttat tcaagtatatcacatgctgt 3060 cagcatattt ggcaccacta ccagccccag ccccctttgc cccgcccccaacacacacac 3120 acacacacac acacacacac acacacacac acacacacac acacacacctttaccttctc 3180 ctgggcatca tctgctcact cacccaccca agcttaatcc ttttccttccctgcaatagt 3240 acctctccta tttttatgtc taggttcccc ctccccctgt taggagatgggagaggtcac 3300 gaaaggaaag aatttgtagc ccctgagcca gcccgggcca cagagcctgccaccagacag 3360 gaaaagccca gggcttacca gcacaggagg agcaaactcg caggcgagcctgggttggcg 3420 ctggtggtcc cgggtcgatg gcccgcccat tcccagaagc cgaggctatagctgcgtcac 3480 ctgccccgcc ctcctcccga gtgaagaccc ctagaggctg agcagaccccaaaggcggtg 3540 caattccatt ggcccaaggc agaggtgagc ggctgctaat cccctcgggaagtgaaggga 3600 cccagagagt ctggtagatg tgggagctgg ggttcagggc gagacagagggtgggatggg 3660 cagaagggtc caggaaaagg aaagtactgg aggggagttg ggacaaaagcagcgaccaag 3720 ggaacatcgc ttcagtgact gaagccaggc aaaaggagcg ggaaggattatatgtagcct 3780 gggacgcttt cataaacact gatgacgtgt ttgtgcaaag caagcaatttgaggagaaac 3840 gcctgggacg tcggaaagaa ggagtgatcg attagtactt gtaagtttaggtgagtttga 3900 gaactaacta acctatacta ttgagggaga aggaagagca ttccagcagcagcagcagca 3960 gcagcaatca gataaaggaa agctttggtt agtttggaaa tgtatgataccattaaaata 4020 acagaagcgc ctccagttct ctgaagagtc agtcccccag ctagtgaagactaagcctac 4080 taagcctttt gctcccgttg gaagcaaaga acgttccttc aatcaggtgaaggctctcct 4140 cagaagattt cctgtctctg cttatgttac aagaggattc aaaagcaagacagaagagct 4200 caggtattgc caactctttt gttaaataca gtttgaggct taagtgtacgggaactcatg 4260 tggtattcat ttacggctct cttctcttat aactaactct taaggtgcatatagtctctt 4320 ctgtttccca gctaccttgt accatctttg tttatctaat aatagcaagctcatctgctt 4380 tttaatcatc acgcagagag tattcaaaaa tattcagtga tgtaacagtgacagtgtagg 4440 catagaagta atcattagta aatcttaatt tgggttaaac tcattcataacagctccagg 4500 ttgggaggga tcactgagcc ttcgccacgt gcgggttaaa gatattttctaacaagagaa 4560 gcagaattct tccttggcca tgctccccat cactgtgtca gtaagcagaggggtgtttcc 4620 aagcagagaa agagcagaca gtgttatgcc tgcaaagtca gagactcagccctcccagct 4680 ggtcagttta ctgtcctccc ggtcattagt tggctctgaa aaggcccatgtgtccttatt 4740 ggcaaggact tgcagacatg ctagaaagaa atttgacctt tttttctagtgggttattac 4800 agctgtaaaa gtattttgga aggttaagcc aaataaataa aacacatattaaataataca 4860 atgttacaaa aattgatcat ataaagaagt acattcataa atgcaatgtgaaaaatatat 4920 ataattttta tctatttact ggtgcaaagt tttctaaatt gcacatgtactatttttata 4980 tttataaaaa tatttttaaa atgtatataa aagtgtaaaa ggctcttggtcaaacaagag 5040 agttaaattt acaaacttta attgtcccga taacattatt atgatctctaatgacaggga 5100 tcctgctttt cattgggaaa tgagaagcta tgaagatatg tttacaataataagcccatt 5160 tagtgataaa gtccaatggg aagctagcac acactggttt ataaagagaacagtttcctg 5220 agtctatgca agtttacact ctagggaata agagttcctc tttctccagatttcactagc 5280 atttgttgtc atcatttatc ttcttgatga tgagcattat aagtggaataagataggatc 5340 tcaaaggaat gtcaatttgg atgccctgaa caatctttca ggtctttctttcagttcact 5400 agtctattca tttattggat aattggggga tggtgttaat ttttttgcagttcttatgga 5460 attccaaaaa acaaaaaaca aacaaacaaa caaaaaacct ctgaaactagaactaccaat 5520 ccattactgg gtatgtaaca aagagaaatc tgcacagaat ttattgctacattgttcatt 5580 attcacgaca gccaagaatg tggaaccaac ttacgtagcc gtcaaaatatgaacggataa 5640 agaaaatgtg gaaatgtgta caacagagtc ccatgtggcc ataaaagagtgaaatcatga 5700 catatgcagg aaatggatgc aactggaaat caattgggct aatcaaaacaagacagactc 5760 aaaaaggaaa caccgtgtag cttctctgac aaacagaagc tagatttacacttgtacgtg 5820 cgcatgtgtg tttagaattt tatttagtta tacactattc taatctgtgagtgtgtataa 5880 aggcatgcat gtaaagcaaa aacaagctag ctggggtggg taggagagaaagcaatgaga 5940 ggagttaata agaacgaagc atagtaacat aggtgccagg atgaaatgcattaatttgta 6000 tgctaactaa accacagaca ggaggcacac gttcaaacca gggtgaaatcccagcacaga 6060 gaaggggaag tagacacaaa gtttcgccac taaccaagaa gccatttgcagttgctgcct 6120 gctgggaggg gcgttccagt tttctccagt ctgacactgt gtataacaaccagttgacaa 6180 tacaaagttg gcatgatgga tggtttttgt gctatttttc attttttttcttactgtttt 6240 gttgttgtgg tggttgttgt ggtggtggct gtggttttca tttgtttcttttgagagaga 6300 gaaggaacat gaaattgggt gggtaggaag ctggaaacga tctggaagaagttggggaaa 6360 gagaaaaatt gtatggagca tatttaaaca aacaaacaaa caaacaaaaggttcattttg 6420 ccacaaaaag gtgtgaatta aattaaccag ttacgactct taaagaaaatattcccaatt 6480 attcccagag ttgctatgta tgctgtgcct aggactttgc ttgaactggccctataactc 6540 tggtgtggtg tcttttcagg atgcagaaga gaggcaggga agtcagctgcttgctgatct 6600 ccctcactgc catctgcctg gtggtcaccc ctgggagcag ggtctgtcctcgccgatgtg 6660 cctgctatgt gcccacagag gtgcactgta catttcggga cctgacctccatcccagacg 6720 ggcatcccag ccaatgtgga acgagtcaat ttagggtgtg tggaccttgcctgatctcct 6780 tctcagagag ggaccactga ttttcctggt actttgcccc ccaaacacctgtgattactt 6840 ttaatagttt tcttctaaaa tgggttcata caaaccttat attgtggagacaatgaacat 6900 tttatcccaa tagtctttta ctagaacttg aagcccctct tagttgtttgggagcctcat 6960 aattatgggg cagctttatt ctgaatgaat tttaaatgaa aaagatacagtttctgttaa 7020 caatcattat gataccaagg aagaggaatt gtcattgaat attttaaaaaagcatttctt 7080 ttgcaattta taaataccca ttacaaaatg gcttacttaa aatacttgccttactaaatc 7140 tgacaaatta tggtgatatt ttgaaggttt atgaaaattt gtttatgtgtataaatgcac 7200 aagaaatggg atatgccatc acctatgtgc cattagtgag catgtacagtatgccaaaca 7260 ctattgttca cgtttggagg aagtaatggg ggtgggggag caacaagggttataaccgta 7320 tacccagtgc cttggaagcg attgcaaaca gtaaagactg acattgtgttctccctatga 7380 gggaggggcc ttgggctgag cactttgcaa tgagcatttg ctcattgtgctggcaggttt 7440 tatgataact tgacccaagc tagagtcact ggagaggaag gaacttcaactgagaacatg 7500 cctgaagaag atcagattat aggcaggcct gtggggcatt ttcttaattagtgattcatg 7560 gggcagggcc cagtccattg ttcgtggtac catttctcag gcactattaaaaaaaaaaaa 7620 acaggctgag caagtgtcaa ggagcaagtc agtgagcagc agccctaatgatctctgcat 7680 cagctcctgc ctccaggttc ctaccctatt tgagttcctg tcctagctccctacagtgat 7740 gaacaatgat gtggaagtat aagccaaata aatcctttct tccccaacttgctgttggtc 7800 atgatgtttc atcacagtga taatagtcct catgaagatg ctggtgtttataacaccttt 7860 ggactaaatt ctgttatcta tagctgagga aaatggagca tagaaagtctccagactaca 7920 ccagagtgta atctgggcct gagcttagaa tcacacccac gtgcactccactgccggggc 7980 ttcttaaccg gaacacagtt gtaaaaggga attttctgtt tgtttccattttgacatgtg 8040 gactttaatt gacgattcat ctgaagctga aaatgatttt ttttccaggtataacagcct 8100 cactagattg acagaaaatg acttttctgg cctgagcaga ctggagttactcatgctgca 8160 cagcaatggc attcacagag tcagtgacaa gaccttctcg ggcttgcagtccttgcaggt 8220 gagataggta gagggtgatg gaggctgaga agagaggtgc aactgtgggttatacccaaa 8280 agctgctgat tcccgtggga gacattctat aagcattcta taaactagaggcagatatca 8340 aggaaggatt tcaattgtaa tgcaatttta tgagaaaatt tgaatattaagaaaatgctg 8400 gggaaaatgc ttacacaatt gcgaggacct aatttaggat ctccaatagccacataaaaa 8460 gcacagcatg gcggcagaca cctgcaattc ctgtccctgg aagcacctgttcagaatccc 8520 agagactcat tggccaaaca ctctattcaa tcaatgaagt ccatattcagtgacaaaact 8580 tgactcagaa actaatgtgg aaagcatcag gaagacagcc aacatctggtctctactcat 8640 gcatgaataa gggatcccag agagaaggga agaaaaagga aggaaggaaggaaggaagga 8700 aggaaggaag gaaggaagga aggaaggaag agagggagga aaggagggagggaaggaagg 8760 aaagggaaag gaaaaaagag atggggaggg agggaaggaa aggaaagggggagaaagaag 8820 agaagaaagg aaaataaata aattttcagg gattattaca cctttaaattttatccataa 8880 aaggtcattt ccacctgttt gtctggaagt agagtgggat cccttatataagggcagtct 8940 ttaacatagt agcattttat aaaccattac aaattttgag ttttctctactttttatcct 9000 ctaccatctt caaactgaaa ctacaattat tcccacaaat gaagaaaatgctgtaagagt 9060 tttcacacac cgaagtggga aacttaagga ttagacaagt ctaacaatgagaatggggag 9120 aacaaaaaga gactgcacag ggagcccttt ctctgcttat aatcttgacacttgagaagc 9180 taattgacgc tgcatgacta ctcaactctt taagcaaaca atgctgttgttcatgaaaag 9240 cacaataaag tacatatgtc ccataatatt catcaaaatt tgcatgcagcacataatagc 9300 aatcaaagca ataacaccca ctgttcacag agactttaaa catgaaactggaactatgtc 9360 tagtgttttg acttagggta catagtatgc tgtgtctgta tgtaccaatgttgatttagg 9420 tcatcagaca gcatttggaa catgtatctt caggaggaat cattcatgtatcctgcatga 9480 aattctccac ctatgtttat tctcttagcc aggtttttct ctgatggagaaacattgggt 9540 ttgaggtttt actcccaggt aacatttagg gaaaagctgt ctatgttctcagtttggctt 9600 ttatttatga gggatgttgg tattccagaa aattctcttt tgaagagattacaatttagg 9660 tcaaaacaga aaaatatgta aaaagttatt gtttttatta gtatttcatgttcttttctt 9720 ttttaaaaat ggtatgctta gaactaatta agattagatt agattagattagaaaataat 9780 cagagaggga tttgatgaat gctaaagcat catgaaaaat tcaaaattttttgcttctaa 9840 ttcagaatca attaaattca tattactata aaagacagca cgccagatgtgtgccagctg 9900 aggagtggat aaactgtgta acgtgagtgc tatgtagaaa cagaaaggagtgaagggttg 9960 atgtgcgctg caacatcttg aaaacattcg gctacatgat ggaagccaggcacaaaaagc 10020 cacatattgc atggttatgt ttatatgaaa tgtttaaaat acatggattcttagcaaaca 10080 gagtaagatg ttacttaggg tcaggaaaag attaaaaaaa aaaaaactattgatgtggaa 10140 tgatcttaat ttggggaaaa gacaatttcc taagacgaaa tagttgaggtagatatagtt 10200 atatccctgt ggatattgta ataaaccagc atgctgtgct ctgagaagggcctaatgaag 10260 gggcaggagg aagtgaaatg agatggtaga aaggaaagtc atataccatggcttctctcg 10320 tgggtggaat ctagatatgt taatatattg acataaagga aggaattgtttagggaagga 10380 tcaaaaccaa caggagtgag ggagacaata ggaaccaatg agaggcaaagttcatggtca 10440 atgtgtgtgg agacaccata ataaaactcc ttttttgttt gctaactaaaaccactaaaa 10500 tctaaaaaca aaacattttt gcacaagaat tatttattat tcaataaagatgtttaaatg 10560 ggggaagttg aagttcattg atagtctcat aaatcttaaa tgtatttaaactgcttttta 10620 cgttttttat tattaattac tcttgctgtc attattatca tcatcattatcgtcatcatc 10680 atcactaatg cttttcacca tacacaaatg taggcagaag agtgtaatccacttagtgag 10740 gcaatcttgg agagggaaag gaagcggatg cggggcagag gcacacaggaggacagtgag 10800 agggaaatga acaagaaaaa atgtggacac atgcacaaaa attccatagtccactacatt 10860 actttgtatt ctaatattaa gaaaataata aacccatttc tgtgcacttatcacccaggc 10920 tcaacagtta tcttggccac agatcctgtc tcactgcatc ctgtccacctgagtccactt 10980 agcgttctga atccaatcca gggcatgatg cttactccta cacagaactaaagattaaag 11040 agagtttaaa agtaaccatg acatctctct gttcctttag cgataagttcttaatattta 11100 tggctgcttg tgtatgttct aatttctcta atattgtcac atttagttggcaactacttt 11160 gtttgaattg agttggagtt aaggtcccat aggattaatc tcaacatatttctatattta 11220 taaacttttc tctctttgtg aaagttcctt tgagaaaaca aatatgcccatatctttctt 11280 tacaggtctt aaaaatgagc tataacaaag tccaaataat tgagaaggatactttgtatg 11340 gactcaggag cttgacccgg ttgcacctgg atcacaacaa cattgagtttatcaaccccg 11400 aggcgtttta cggactcacc ttgctccgct tggtacatct agaaggaaaccggctgacaa 11460 agctccatcc agacacattt gtctctttga gctatctcca gatatttaaaacctccttca 11520 ttaagnacct gtacttgtat gataacttca ttgacctccc tcccaaaagaaatggtctcc 11580 tctatgccaa acctagaaag cctttacttg catggaaacc catggacctgtgactgccat 11640 ttaaagtggt tgtccgagtg gatgcaggga aacccaggta actatcttgtttgtttgttt 11700 ctttttttat arkacgtatt ttcctcaatt tcatttagaa tgatatcccaaaagtccccc 11760 ataacctccc ccccacttcc ctacctaccc attcccattt tttggccctggcattcccct 11820 gtactggggc atataaagtt tgcgtgtcca atggacctct ctttccagtgatggccaact 11880 aggccatctt ttgatacata tgcagctaga gtcaagagct ctggggtactggttagttca 11940 taatgttgtt gcacctacag ggttgaa 11967 4 2404 DNA homosapiens 4 tgggcagctg gatccacgtc taccctaatg gatccctgtt tattggatcagtaacagaaa 60 aagacagtgg tgtctacttg tgtgtggcaa gaaacaaaat gggggatgatctgatactga 120 tgcatgttag cctaagactg aaacctgcca aaattgacca caagcagtattttagaaagc 180 aagtgctcca tgggaaagat ttccaagtag attgcaaagc ttccggctccccagtgccag 240 agatatcttg gagtttgcct gatggaacca tgatcaacaa tgcaatgcaagccgatgaca 300 gtggccacag gactaggaga tatacccttt tcaacaatgg aactttatacttcaacaaag 360 ttggggtagc ggaggaagga gattatactt gctatgccca gaacaccctagggaaagatg 420 aaatgaaggt ccacttaaca gttataacag ctgctccccg gataaggcagagtaacaaaa 480 ccaacaagag aatcaaagct ggagacacag ctgtccttga ctgtgaggtcactggggatc 540 ccaaaccaaa aatattttgg ttgctgcctt ccaatgacat gatttccttctccattgata 600 ggtacacatt tcatgccaat gggtctttga ccatcaacaa agtgaaactgctcgattctg 660 gagagtacgt atgtgtagcc cgaaatccca gtggggatga caccaaaatgtacaaactgg 720 atgtggtctc taaacctcca ttaatcaatg gtctgtatac aaacagaactgttattaaag 780 ccacagctgt gagacattcc aaaaaacact ttgactgcag agctgaagggacaccatctc 840 ctgaagtcat gtggatcatg ccagacaata ttttcctcac agccccatactatggaagca 900 gaatcacagt ccataaaaat ggaaccttgg aaattaggaa tgtgaggctttcagattcag 960 ccgactttat ctgtgtggcc cgaaatgaag gtggagagag cgtgttggtagtacagttag 1020 aagtactgga aatgctgaga agaccgacat ttagaaatcc atttaatgaaaaaatagttg 1080 cccagctggg aaagtccaca gcattgaatt gctctgttga tggtaacccaccacctgaaa 1140 taatctggat tttaccaaat ggcacacgat tttccaatgg accacaaagttatcagtatc 1200 tgatagcaag caatggttct tttatcattt ctaaaacaac tcgggaggatgcaggaaaat 1260 atcgctgtgc agctaggaat aaagttggct atattgagaa attagtcatattagaaattg 1320 gccagaagcc agttattctt acctatgcac cagggacagt aaaaggcatcagtggagaat 1380 ctctatcact gcattgtgtg tctgatggaa tccctaagcc aaatatcaaatggactatgc 1440 caagtggtta tgtagtagac aggcctcaaa ttaatgggaa atacatattgcatgacaatg 1500 gcaccttagt cattaaagaa gcaacagctt atgacagagg aaactatatctgtaaggctc 1560 aaaatagtgt tggtcataca ctgattactg ttccagtaat gattgtagcctaccctcccc 1620 gaattacaaa tcgtccaccc aggagtattg tcaccaggac aggggcagcctttcagctcc 1680 actgtgtggc cttgggagtt cccaagccag aaatcacatg ggagatgcctgaccactccc 1740 ttctctcaac ggcaagtaaa gagaggacac atggaagtga gcagcttcacttacaaggta 1800 ccctagtcat tcagaatccc caaacctccg attctgggat atacaaatgcacagcaaaga 1860 acccacttgg tagtgattat gcagcaacgt atattcaagt aatctgacatgaaataataa 1920 agtcaacaac atctgggcag aatttatttt ttggaagaag tttaatcaaaggcagccata 1980 ggcatgtaaa tgaatttgaa tacatttaca gtattaaatt tacaatgaacatgcaaaata 2040 aaaggacttg taaataaatg cattatgaac tgatgataag tctctgtggatctcaaagca 2100 aactcttaac ttaaggcact ttgctgattt atttaatgga tctcaaaacaaacttttaac 2160 ttaaggcact tttattttgc caacaaataa caataaacaa acattgaaacggttcactat 2220 aaaataacaa atggctaatg tacctgaatt tttcagtaaa aaaatgaacttctaatacca 2280 gttgcctagt gtccacctcc tatcaatgtt acaagcatgg cactcagaacagagacaatg 2340 gaaaatatta aatctgcaat ctttatgatg taaatttacc atcctgatgtataaatattt 2400 tgtg 2404 5 8883 DNA rattus sp misc_feature (1)..(8916)n can be any amino acid 5 cgagagacga cagaaggtta cggctgcgag aagacgacagaagggtccag aaaaaggaaa 60 gtgctggagg ggagtgggga caaaagcagc gaccaagtgaatgtcacttc agtgactgag 120 gccaggcaaa acgcgcggga aggattttgt gtagcttgggaccctttcat agacactgat 180 gacacgttta cgcaaaatag aaatttgagg agaaacgcctgggccttcgg aaaggagtga 240 ttgattagta cttgcaagtt taggtgactt taaggagaactaactaatgt atactattga 300 gggaggagga agagcattac agagtttcca gcagcagcaggaaagctttg gttaatttgg 360 aaatggatga tagcattaaa ataacagaag cgcctccaggtctctgaagc ttcagtcccc 420 cagctgaaag ccagaaaaga ctaagcccac taagccttttgatccctttg gaagcaaaga 480 actttccttc cctggggtga agactctcct cagaagatttcctgtctctg cctatgttac 540 aagaggaatc aaaaccaaga cagaagagct caggatgcaggtgagaggca gggaagtcag 600 cggcttgttg atctccctca ctgctgtctg cctggtggtcacccctggga gcagggcctg 660 tcctcgccgc tgtgcctgct atgtgcccac agaggtgcactgtacatttc ggtacctgac 720 ctccatccca gatggcatcc cggccaatgt ggaacgaataaatttaggat ataacagcct 780 tactagattg acagaaaacg actttgatgg cctgagcaaactggagttac tcatgctgca 840 cagtaatggc attcacagag tcagtgacaa gaccttctcgggcttgcagt ccttgcaggt 900 cttaaaaatg agctataaca aagtccaaat cattcggaaggatactttct acggactcgg 960 gagcttggtc cggttgcacc tggatcacaa caacattgaattcatcaacc ctgaggcctt 1020 ttatggactt acctcgctcc gcttggtaca tttagaaggaaaccggctca caaagctcca 1080 tccagacaca tttgtctcat taagctatct ccagatatttaaaacctctt tcattaagta 1140 cctgttcttg tctgataact tcctgacctc cctcccaaaagaaatggtct cctacatgcc 1200 aaacctagaa agcctgtatt tgcatggaaa cccatggacctgtgactgcc atttaaagtg 1260 gttgtctgag tggatgcagg gaaacccaga tataataaaatgcaagaaag acagaagctc 1320 ttccagtcct cagcaatgtc ccctttgcat gaaccccaggatctctaaag gcagaccctt 1380 tgctatggta ccatctggag ctttcctatg tacaaagccaaccattgatc catcactgaa 1440 gtcaaagagc ctggttactc aggaggacaa tggatctgcctccacctcac ctcaagattt 1500 catagaaccc tttggctcct tgtctttgaa catgacananntntctggaa ataaggccga 1560 catggtctgt agtatccaaa agccatcaag gacatcaccaactgcattca ctgaagaaaa 1620 tgactacatc atgctaaatg cgtcattttc cacaaatcttgtgtgcagtg tagattataa 1680 tcacatccag ccagtgtggc aacttctggc tttatacagtgactctcctc tgatactaga 1740 aaggaagccc cagcttaccg agactccttc actgtcttctagatataaac aggtggctct 1800 taggcctgaa gacattttta ccagcataga ggctgatgtcagagcagacc ctttttggtt 1860 ccaacaagaa aaaattgtct tgcagctgaa cagaactgccaccacactta gcacattaca 1920 gatccagttt tccactgatg ctcaaatcgc tttaccaagggcggagatga gagcggagag 1980 actcaaatgg accatgatcc tgatgatgaa caatcccaaactggaacgca ctgtcctggt 2040 tggcggcact attgccctga gctgtccagg caaaggcgacccttcacctc acttggaatg 2100 gcttctagct gatgggagta aagtgagagc cccttacgttagcgaggatg ggcgaatcct 2160 aatagacaaa aatgggaagt tggaactgca gatggctgacagctttgatg caggtcttta 2220 ccactgcata agcaccaatg atgcagatgc ggatgttctcacatacagga taactgtggt 2280 agagccctat ggagaaagca cacatgacag tggagtccagcacacagtgg ttacgggtga 2340 gacgctcgac cttccatgcc tttccacggg tgttccagatgcttctatta gctggattct 2400 tccagggaac actgtgttct ctcagccatc aagagacaggcaaattctta acaatgggac 2460 cttaagaata ttacaggtta cgccaaaaga tcaaggtcattaccaatgtg tggctgccaa 2520 cccatcaggg gccgactttt ccagttttaa agtttcagttcaaaagaaag gccaaaggat 2580 ggttgagcat gacagggagg caggtggatc tggacttggagaacccaact ccagtgtttc 2640 ccttaagcag ccagcatctt tgaaactctc tgcatcagctttgacagggt cagaggctgg 2700 aaaacaagtc tccggtgtac ataggaagaa caaacatagagacttaatac atcggcggcg 2760 tggggattcc acgctccggc gattcaggga gcataggaggcagctccctc tctctgctcg 2820 gagaattgac ccgcaacgct gggcagcact tctagaaaaagccaaaaaga attctgtgcc 2880 aaaaaagcaa gaaaatacca cagtaaagcc agtgccactggctgttcccc tcgtggaact 2940 cactgacgag gaaaaggatg cctctggcat gattcctccagatgaagaat tcatggttct 3000 gaaaactaag gcttctggtg tcccaggaag gtcaccaactgctgactctg gaccagtaaa 3060 tcatggtttt atgacgagta tagcttctgg cacagaagtctcaactgtga atccacaaac 3120 actacaatct gagcaccttc ctgatttcaa attatttagtgtaacaaacg gtacagctgt 3180 gacaaagagt atgaacccat ccatagcaag caaaatagaagatacaacca accaaaaccc 3240 aatcattatc tttccatcag tagctgaaat tcgagattctgctcaggcag gaagagcatc 3300 ttcccaaagt gcacaccctg taacaggggg aaacatggctacctatggcc ataccaacac 3360 atatagtagc tttaccagca aagccagtac agtcttgcagccaataaatc caacagaaag 3420 ttatggacct cagataccta ttacaggagt cagcagacctagcagtagtg acatctcttc 3480 tcacactact gcagacccta gcttctccag tcacccttcaggttcacaca ccactgcctc 3540 gtctttattt cacattccta gaaacaacaa tacaggtaacttccccttgt ccaggcactt 3600 gggaagagag aggacaattt ggagcagagg gagagttaaaaacccacata gaaccccagt 3660 tctccgacgg catagacaca ggactgtgag gccagcaatcaagggacctg ctaacaaaaa 3720 tgtgagccaa gttccagcca cagagtaccc tgggatgtgccacacatgtc cttccgcaga 3780 ggggctcaca gtggctactg cagcactgtc agttccaagttcatcccaca gtgccctccc 3840 caaaactaat aatgttgggg tcatagcaga agagtctaccactgtggtca agaaaccact 3900 gttactattt aaggacaaac aaaatgtaga tattgagataataacaacca ctacaaaata 3960 ttccggaggg gaaagtaacc acgtgattcc tacggaagcaagcatgactt ctgctccaac 4020 atctgtatcc ctggggaaat ctcctgtaga caatagtggtcacctgagca tgcctgggac 4080 catccaaact gggaaagatt cagtggaaac aacaccacttcccagccccc tcagcacacc 4140 ctcaatacca acaagcacaa aattctcaaa gaggaaaactcccttgcacc agatctttgt 4200 aaataaccag aagaaggagg ggatgttaaa gaatccatatcaattcggtt tacaaaagaa 4260 cccagccgca aagcttccca aaatagctcc tcttttacccacaggtcaga gttccccctc 4320 agattctaca actctcttga caagtccgcc accagctctgtctacaacaa tggctgccac 4380 tcagaacaag ggcactgaag tagtatcagg tgccagaagtctctcagcag ggaagaagca 4440 gcccttcacc aactcctctc cagtgcttcc tagcaccataagcaagagat ctaatacatt 4500 aaacttcttg tcaacggaaa cccccacagt gacaagtcctactgctactg catctgtcat 4560 tatgtctgaa acccaacgaa caagatccaa agaagcaaaagaccaaataa aggggcctcg 4620 gaagaacaga aacaacgcaa acaccacccc caggcaggtttctggctata gtgcatactc 4680 agctctaaca acagctgata cccccttggc tttcagtcattccccacgac aagatgatgg 4740 tggaaatgta agtgcagttg cttatcactc aacaacctctcttctggcca taactgaact 4800 gtttgagaag tacacccaga ctttgggaaa tacaacagctttggaaacaa cgttgttgag 4860 caaatcacag gagagtacca cagtgaaaag agcctcagacacaccaccac cactcctcag 4920 cagtggggcg cccccagtgc ccactccttc cccacctccttttactaagg gtgtggttac 4980 agacagcaaa gtcacatcag ctttccagat gacgtcaaatagagtggtca ccatatatga 5040 atcttcaagg cacaatacag atctgcagca accctcagcagaggctagcc ccaatcctga 5100 gatcataact ggaaccactg actctccctc taatctgtttccatccactt ctgtgccagc 5160 actaagggta gataaaccac agaattctaa atggaagccctctccctggc cagaacacaa 5220 atatcagctc aagtcatact ccgaaaccat tgagaagggcaaaaggccag cagtaagcat 5280 gtccccccac ctcagccttc cagaggccag cactcatgcctcacactgga atacacagaa 5340 gcatgcagaa aagagtgttt ttgataagaa acctggtcaaaacccaactt ccaaacatct 5400 gccttacgtc tctctaccta agactctatt gaaaaagccaagaataattg gaggaaaggc 5460 tgcaagcttt acagttccag ctaattcaga cgtttttcttccttgtgagg ctgttggaga 5520 cccactgccc atcatccact ggaccagagt ttcatcagganttgaaatat cccaagggac 5580 acagaaaagc cggttccacg tgcttcccaa tggcaccttgtccatccaga gggtcagtat 5640 tcaggaccgt ggacagtacc tgtgctctgc atttaatccactgggcgtag accattttca 5700 tgtctctttg tctgtggttt tttacccggc aaggattttggacagacatg tcaaggagat 5760 cacagttcac tttggaagta ctgtggaact aaagtgcagagtggagggta tgccgaggcc 5820 tacggtttcc tggatacttg caaaccaaac ggtggtctcagaaacggcca agggaagcag 5880 aaaggtctgg gtaacacctg atggaacatt gatcatctataatctgagtc tttatgatcg 5940 tggtttttac aagtgtgtgg ccagcaaccc atctggccaggattcactgt tggttaagat 6000 acaagtcatc acagctcccc ctgtcattat agagcaaaagaggcaagcca tcgttggggt 6060 tttaggtgga agtttgaaac tgccctgcac tgcaaaaggaactccccagc ctagtgttca 6120 ctgggtcctt tatgatggga ctgaactaaa accattgcagttgactcatt ccagattttt 6180 cttgtatcca aatggaactc tgtatataag aagcatcgctccttcagtga ggggcactta 6240 tgagtgcatt gccaccagct cctcaggctc agagagaagggtagtgattc ttactgtgga 6300 agagggagag acaatcccca ggatagaaac tgcctctcagaaatggactg aggtgaattt 6360 gggtgagaaa ttactactga actgctcagc tactggggatccaaagccta gaataatctg 6420 gaggctgcca tccaaggctg tcatcgacca gtggcacagaatgggcagcc gaatccacgt 6480 ctacccaaat ggatccttgg tggttgggtc agtgacggaaaaagacgctg gtgactactt 6540 atgtgtggca agaaacaaaa tgggagatga cctagtcctgatgcatgtcc gcctgagatt 6600 gacacctgcc aaaattgaac agaagcagta ttttaagaagcaagtgctcc atgggaaaga 6660 tttccaagtt gactgcaagg cctctggctc ccctgtgcctgaggtatcct ggagtttgcc 6720 tgatgggaca gtgctcaaca atgtagccca agctgatgacagtggctata ggaccaagag 6780 gtacaccctt ttccacaatg gaaccttgta tttcaacaacgttgggatgg cagaggaagg 6840 agattatatc tgctctgccc agaacacctt agggaaagatgagatgaaag tccacctaac 6900 agttctaaca gccatcccac ggataaggca aagctacaagaccaccatga ggctcagggc 6960 tggagaaaca gctgtccttg actgcgaggt cactggggaaccgaagccca atgtattttg 7020 gttgctgcct tccaacaatg tcatttcatt ctccaatgacaggttcacat ttcatgccaa 7080 tagaactttg tccatccata aagtgaaacc acttgactctggggactatg tgtgcgtagc 7140 tcagaatcct agtggggatg acactaagac atacaaactggacattgtct ctaaacctcc 7200 attaatcaat ggcctgtatg caaacaagac tgttattaaagccacagcca ttcggcactc 7260 caaaaaatac tttgactgca gagcagatgg gatcccatcttcccaggtca cgtggattat 7320 gccaggcaat attttcctcc cagctccata ctttggaagcagagtcacgg tccatccaaa 7380 tggaaccttg gagatgagga acatccggct ttctgactctgcggacttca cctgtgtggt 7440 tcggagcgag ggaggagaga gtgtgttggt agtgcagttagaagtcctag aaatgctgag 7500 aagaccaaca ttcagaaacc cattcaacga aaaagtcatcgcccaagctg gcaagcccgt 7560 agcactgaac tgctctgtgg atgggaaccc cccacctgaaattacctgga tcttacctga 7620 cggcacacag tttgctaaca gaccacacaa ttccccgtatctgatggcag gcaatggctc 7680 tctcatcctt tacaaagcaa ctcggaacaa gtcagggaagtatcgctgtg cagccaggaa 7740 taaggttggc tacatcgaga aactcatcct gttagagattgggcagaagc cagtcattct 7800 gacatacgaa ccagggatgg tgaagagcgt cagtggggaaccgttatcac tgcattgtgt 7860 gtctgatggg atccccaagc caaatgtcaa gtggactacaccgggtggcc atgtaatcga 7920 caggcctcaa gtggatggaa aatacatact gcatgaaaatggcacgctgg tcatcaaagc 7980 aacaacagct cacgaccaag gaaattatat ctgtagggctcaaaacagtg ttggccaggc 8040 agttattagc gtgtcagtga tggttgtggc ctaccctccccgaatcataa actacctacc 8100 caggaacatg ctcaggagga caggggaagc catgcagctccactgtgtgg ccttgggaat 8160 ccccaagcca aaagtcacct gggagacgcc aagacactccctgctctcaa aagcaacagc 8220 aagaaaaccc catagaagtg agatgcttca cccacaaggtacgctggtca ttcagaatct 8280 ccaaacctcg gattccggag tctataagtg cagagctcagaacctacttg ggactgatta 8340 cgcaacaact tacatccagg tactctgaca ggaagggggagactaaaatt caacagaagt 8400 ccacatccac agggtttatt ttttggaaga agtttaatcaaaggcagcca taggcatgta 8460 aatgagtctg aatacattta cagtattaaa tttacaatggacatgcgatg agacttgtaa 8520 atgaaagcat tgtgaactga aaccgagtct ctgtggatctcaaagcaaac tcttaactta 8580 aggcactttg attttgccaa caaataataa caaacattaagagaaaaaaa tgatccacta 8640 cgaaataaca aacggctaat gcacctgaat tctcagtaaaaagacctttc tctcgctaac 8700 agttgccagc tgcctcgtgt ctgtttccta ccaatgtcacaaacatcgca cacagggtga 8760 atggagtcaa cgggaaagat taagtttgcg gtctgtgtaaatctcaatgt acaaatattc 8820 tgtcnctggt ttataaacat tttgataaaa ccgaaaaaaaaaaaaaaaaa aaaaaaaaaa 8880 aaa 8883 6 8262 DNA homo sapiens misc_feature(1)..(8262) ′n′ can be any nucleotide ′a′, ′c′, ′g′ or ′t′. 6 atgaaggtaaaaggcagagg aatcacctgc ttgctggtct cctttgctgt gatctgcctg 60 gtcgccacccctgggggcaa ggcctgtcct cgccgctgtg cctgttatat gcctacggag 120 gtacactgcacatttcggta cctgacttcc atcccagaca gcatcccgcc caatgtggaa 180 cgcatcaatttaggatacaa cagcttggtt agattgatgg aaacagattt ttctggcctg 240 accaaactggagttactcat gcttcacagc aatggcattc acacaatccc tgacaagacc 300 ttctcagatttgcaggcctt gcaggtctta aaaatgagct ataataaagt ccgaaaactt 360 cagaaagatactttttatgg cctcaggagc ttgacacgat tgcacatgga ccacaacaat 420 attgagtttataaacccaga ggttttttat gggctcaact ttctccgcct ggtgcacttg 480 gaaggaaatcagctcactaa gctccaccca gatacatttg tctctttgag ctacctccag 540 atatttaaaatctctttcat taagttccta tacttgtctg ataacttcct gacctccctc 600 cctcaagagatggtctccta tatgcctgac ctagacagcc tttacctgca tggaaaccca 660 tggacctgtgattgccattt aaagtggttg tctgactgga tacaggnnnn nccagatgta 720 ataaaatgcaaaaaagatag aagtccctct agtgctcagc agtgtccact ttgcatgaac 780 cctaggacttctaaaggcaa gccgttagct atggtctcag ctgcagcttt ccagtgtgcc 840 aagccaaccattgactcatc cctgaaatca aagagcctga ctattctgga agacagtagt 900 tctgctttcatctctcccca aggtttcatg gcaccctttg gctccctcac tttgaatatg 960 acagatcagtctggaaatga agctaacatg gtctgcagta ttcaaaagcc ctcaaggaca 1020 tcacccattgcattcactga agaaaatgac tacatcgtgc taaatacttc attttcaaca 1080 tttttggtgtgcaacataga ttacggtcac attcagccag tgtggcaaat tttggctttg 1140 tacagtgattctcctctgat actagaaagg agccacttgc ttagtgaaac accgcagctc 1200 tattacaaatataaacaggt ggctcctaag cctgaagaca tttttaccaa catagaggca 1260 gatctcagagcagatccctc ttggttaatg caagaccaaa tttccttgca gctgaacaga 1320 actgccaccacattcagtac attacagatc cagtactcca gtgatgctca aatcacttta 1380 ccaagagcagagatgaggcc agtgaaacac aaatggacta tgatttcaag ggataacaat 1440 actaagctggaacatactgt cttggtaggt ggaaccgttg gcctgaactg cccaggccaa 1500 ggagaccccaccccacacgt ggattggctt ctagctgatg gaagtaaagt gagagcccct 1560 tatgtcagtgaggatggacg gatcctaata gacaaaagtg gaaaattgga actccagatg 1620 gctgatagttttgacacagg cgtatatcac tgtataagca gcaattatga tgatgcagat 1680 attctcacctataggataac tgtggtagaa cctttggtcg aagcctatca ggaaaatggg 1740 attcatcacacagttttcat tggtgaaaca cttgatcttc catgccattc tactggtatc 1800 ccagatgcctctattagctg ggttattcca ggaaacaatg tgctctatca gtcatcaaga 1860 gacaagaaagttctaaacaa tggcacatta agaatattac aggtcacccc gaaagaccaa 1920 ggttattatcgctgtgtggc agccaaccca tcaggggttg attttttgat tttccaagtt 1980 tcagtcaagatgaaaggaca aaggcccttg gagcatgatg gagaaacaga gggatctgga 2040 cttgatgagtccaatcctat tgctcatctt aaggagccac caggtgcaca actccgtaca 2100 tctgctctgatggaggctga ggttggaaaa cacacctcaa gcacaagtaa gaggcacaac 2160 tatcgggaattaacactcca gcgacgtgga gattcaacac atcgacgttt tagggagaat 2220 aggaggcatttccctccctc tgctaggaga attgacccac aacattgggc ggcactgttg 2280 gagaaagctaaaaagaatgc tatgccagac aagcgagaaa ataccacagt gagcccaccc 2340 ccagtggtcacccaactccc aaacatacct ggtgaagaag acgattcctc aggcatgctc 2400 gctctacatgaggaatttat ggtcccggcc actaaagctt tgaaccttcc agcaaggaca 2460 gtgactgctgactccagaac aatatctgat agtcctatga caaacataaa ttatggcaca 2520 gaactctccgttgtgaattc acaaatacta ccacctgaag aacccacaga tttcaaactg 2580 tctactgctattaaaactac agccatgtca aagaatataa acccaaccat gtcaagccaa 2640 atacaaggcacaaccaatca acattcatcc actgtctttc cactgctact tggagcaact 2700 gaatttcaggactctgacag agggaagagg aagagagcat ttccagtaac ccccaataac 2760 agtaaggactatgatcaaag atgntcaatg tcaaanatgc ttagtagcac caccaacaaa 2820 ctattattagagtcagtaaa taccacaaat agtcatcaga catctgtaag agaagtgagt 2880 gaacccaggcacaatcactt ctattctcac actactcaaa tacttagcac ctccacgttc 2940 ccttcagatccacacacagc tgctcattct cagtttccga tccctagann naatagtaca 3000 gttaacatcccgctgttcag acgctttggg aggcagagga aaattggcgg aagggggcgg 3060 attatcagcccatatagaac tccagttctg cgacggcata gatacagcat tttcaggtca 3120 acaaccagaggttcttctga aaaaagcact actgcattct cagccacagt gctcaatgtg 3180 acatgtctgtcctgtcttcc cagggagagg ctcaccactg ccacagcagc attgtctttt 3240 ccaagtgctgctcccatcac cttccccaaa gctgacattg ctagagtccc atcagaagag 3300 tctacaactctagtccagaa tccactatta ctacttgaga acaaacccag tgtagannnn 3360 gaaannacaacacccacaat aaaatattca ggactngaaa tttcccaagt gactccaact 3420 ggtgcagtcatgacatatgc tccaacatcc atacccatgg aaaaaactca caaagtaaac 3480 gccagttacccacgtgtgtc tagcaccaat gaagctaaaa gagattcagt gattacatcg 3540 tcactttcaggtgctatcac caagccacca atgactatta tagccattac aaggttttca 3600 agaaggaaaattccctggca acagaacttt gtaaataacc ataacccaaa aggcagatta 3660 aggaatcaacataaagttag tttacaaaaa agcacagctg tgatgcttcc taaaacatct 3720 cctgctttaccacagagaca aagttcccct ttccatttca ccacactttc aacaagtgtg 3780 atgcaaattccatctaatac cttgactacc gctcaccaca ctacgaccaa aacacacaat 3840 cctggaagtcttccaacaaa gaaggagctt cccttcccac cccttaaccc tatgcttcct 3900 agtattataagcaaagactc aagtacaaaa agcatcatat caacgcaaac agcaaccgca 3960 acaactcctaccttccctgc atctgtcatc acttatgaaa cccaaacaga gagatctaga 4020 gcacaaacaatacaaagaga aggacctcaa aagaagaaca ggactgaccc aaacatctct 4080 ccagaccagagttctggctt cactacaccc actgctatga cnacctcctn ngctctnnnn 4140 gcattcactcattccccacc agaaaacaca actgggattt caagcacaat cagttttcat 4200 tcaagaactcttaatctgac agatgtgatt gaagaactag cccaagcaag tactcagact 4260 ttgaagagcacaattgcttc tgaaacaact ttgtccagca aatcacacca gagtaccaca 4320 actaggaaagcatcattaga cactcaacca ccaccattct tgagcagcag tgctactcta 4380 atgccagttcccatctcccc tccctttact cagagagcag ttactgacaa cgtggcgact 4440 cccatttccgggcttatgac aaatacagtg gtcaagctgc acgaatcctc aaggcacaat 4500 ccnnnnnnncaaatgccaag ttcacnnaat tgngaaccnn nnactcnnnn nacttcatct 4560 acntctaatctgttacattc tactcccatg ccagcactaa caacagttaa atcacagaat 4620 tccaaattaactccatctcc ctgggcagaa taccaatttt ggcacaaacc atactcagac 4680 attgctgaaaaaggcaaaaa gccagaagta agcatgttgg ctactacagg cctgtccgag 4740 gccaccactcttgtttcaga ttgggatgga cagaagaaca caaagaagag tgactttgat 4800 aagaaaccagttcaagaagc aacaacttcc aaactccttc cctttgactc tttgtctagg 4860 tatatatttgaaaagcccag gatagttgga ggaaaagctg caagttttac tattccagct 4920 aactcagatgcctttcttcc ctgtgaagct gttggaaatc ccctgcccac cattcattgg 4980 accagagtnnnntcaggact tgatttatct aagaggaaac agaatagcag ggtccaggtt 5040 ctccccaatggtaccctgtc catccagagg gtggaaattc aggaccgcgg acagtacttg 5100 tgttccgcatccaatctgtt tggcacagac caccttcatg tcaccttgtc tgtggtttcc 5160 tatcctcccaggatcctgga gagacgtacc aaagagatca cagttcattc cggaagcact 5220 gtggaactgaagtgcagagc agaaggtagg ccaagcccta cagttacctg gattcttgca 5280 aaccaaacagttgtctcaga atcatcccag ggaagtaggc aggctgtggt gacggttgac 5340 ggaacattggtcctccacaa tctcagtatt tatgaccgtg gcttttacaa atgtgtggcc 5400 agcaacccaggtggccagga ttcactgctg gttaaaatac aagtcattgc agcaccacct 5460 gttattctagagcaaaggag gcaagtcatt gtaggcactt ggggtgaaag tttaaaactg 5520 ccctgtactgcaaaaggaac tcctcagccc agcgtttact gggtcctctc tgatggcact 5580 gaagtgaaaccattacagtt taccaattcc aagttgttct tattttcaaa tgggactttg 5640 tatataagaaacctagcctc ttcagacagg ggcacttatg aatgcattgc taccagttcc 5700 actggttcggagcgaagagt agtaatgctt acaatggaag agcgagtgac cagccccagg 5760 atagaagctgcatcccagaa aaggactgaa gtgaattttg gggacaaatt actactgaac 5820 tgctcagccactggggagcc caaaccccaa ataatgtgga ggttaccatc caaggctgtg 5880 gtcgaccagtgggcagctgg atccacgtct accctaatgg atccctgttt attggatcag 5940 taacagaaaaagacagtggt gtctacttgt gtgtggcaag aaacaaaatg ggggatgatc 6000 tgatactgatgcatgttagc ctaagactga aacctgccaa aattgaccac aagcagtatt 6060 ttagaaagcaagtgctccat gggaaagatt tccaagtaga ttgcaaagct tccggctccc 6120 cagtgccagagatatcttgg agtttgcctg atggaaccat gatcaacaat gcaatgcaag 6180 ccgatgacagtggccacagg actaggagat ataccctttt caacaatgga actttatact 6240 tcaacaaagttggggtagcg gaggaaggag attatacttg ctatgcccag aacaccctag 6300 ggaaagatgaaatgaaggtc cacttaacag ttataacagc tgctccccgg ataaggcaga 6360 gtaacaaaaccaacaagaga atcaaagctg gagacacagc tgtccttgac tgtgaggtca 6420 ctggggatcccaaaccaaaa atattttggt tgctgccttc caatgacatg atttccttct 6480 ccattgataggtacacattt catgccaatg ggtctttgac catcaacaaa gtgaaactgc 6540 tcgattctggagagtacgta tgtgtagccc gaaatcccag tggggatgac accaaaatgt 6600 acaaactggatgtggtctct aaacctccat taatcaatgg tctgtataca aacagaactg 6660 ttattaaagccacagctgtg agacattcca aaaaacactt tgactgcaga gctgaaggga 6720 caccatctcctgaagtcatg tggatcatgc cagacaatat tttcctcaca gccccatact 6780 atggaagcagaatcacagtc cataaaaatg gaaccttgga aattaggaat gtgaggcttt 6840 cagattcagccgactttatc tgtgtggccc gaaatgaagg tggagagagc gtgttggtag 6900 tacagttagaagtactggaa atgctgagaa gaccgacatt tagaaatcca tttaatgaaa 6960 aaatagttgcccagctggga aagtccacag cattgaattg ctctgttgat ggtaacccac 7020 cacctgaaataatctggatt ttaccaaatg gcacacgatt ttccaatgga ccacaaagtt 7080 atcagtatctgatagcaagc aatggttctt ttatcatttc taaaacaact cgggaggatg 7140 caggaaaatatcgctgtgca gctaggaata aagttggcta tattgagaaa ttagtcatat 7200 tagaaattggccagaagcca gttattctta cctatgcacc agggacagta aaaggcatca 7260 gtggagaatctctatcactg cattgtgtgt ctgatggaat ccctaagcca aatatcaaat 7320 ggactatgccaagtggttat gtagtagaca ggcctcaaat taatgggaaa tacatattgc 7380 atgacaatggcaccttagtc attaaagaag caacagctta tgacagagga aactatatct 7440 gtaaggctcaaaatagtgtt ggtcatacac tgattactgt tccagtaatg attgtagcct 7500 accctccccgaattacaaat cgtccaccca ggagtattgt caccaggaca ggggcagcct 7560 ttcagctccactgtgtggcc ttgggagttc ccaagccaga aatcacatgg gagatgcctg 7620 accactcccttctctcaacg gcaagtaaag agaggacaca tggaagtgag cagcttcact 7680 tacaaggtaccctagtcatt cagaatcccc aaacctccga ttctgggata tacaaatgca 7740 cagcaaagaacccacttggt agtgattatg cagcaacgta tattcaagta atctgacatg 7800 aaataataaagtcaacaaca tctgggcaga atttattttt tggaagaagt ttaatcaaag 7860 gcagccataggcatgtaaat gaatttgaat acatttacag tattaaattt acaatgaaca 7920 tgcaaaataaaaggacttgt aaataaatgc attatgaact gatgatactg atttatttaa 7980 tggatctcaaaacaaacttt taacttaagg cacttttatt ttgccaacaa ataacaataa 8040 acaaacattgaaacggttca ctataaaata acaaatggct aatgtacctg aatttttcag 8100 taaaaaaatgaacttctaat accagttgcc tagtgtccac ctcctatcaa tgttacaagc 8160 atggcactcagaacagagac aatggaaaat attaaatctg caatctatgt ataaatattt 8220 tgtggtttataaattttttt gctaaaacct acagaaaata ag 8262 7 8883 DNA Rattus sp.misc_feature (1)..(8916) ′n′ can be any nucleotide ′a′, ′c′, ′g′ or ′t′.7 cgagagacga cagaaggtta cggctgcgag aagacgacag aagggtccag aaaaaggaaa 60gtgctggagg ggagtgggga caaaagcagc gaccaagtga atgtcacttc agtgactgag 120gccaggcaaa acgcgcggga aggattttgt gtagcttggg accctttcat agacactgat 180gacacgttta cgcaaaatag aaatttgagg agaaacgcct gggccttcgg aaaggagtga 240ttgattagta cttgcaagtt taggtgactt taaggagaac taactaatgt atactattga 300gggaggagga agagcattac agagtttcca gcagcagcag gaaagctttg gttaatttgg 360aaatggatga tagcattaaa ataacagaag cgcctccagg tctctgaagc ttcagtcccc 420cagctgaaag ccagaaaaga ctaagcccac taagcctttt gatccctttg gaagcaaaga 480actttccttc cctggggtga agactctcct cagaagattt cctgtctctg cctatgttac 540aagaggaatc aaaaccaaga cagaagagct caggatgcag gtgagaggca gggaagtcag 600cggcttgttg atctccctca ctgctgtctg cctggtggtc acccctggga gcagggcctg 660tcctcgccgc tgtgcctgct atgtgcccac agaggtgcac tgtacatttc ggtacctgac 720ctccatccca gatggcatcc cggccaatgt ggaacgaata aatttaggat ataacagcct 780tactagattg acagaaaacg actttgatgg cctgagcaaa ctggagttac tcatgctgca 840cagtaatggc attcacagag tcagtgacaa gaccttctcg ggcttgcagt ccttgcaggt 900cttaaaaatg agctataaca aagtccaaat cattcggaag gatactttct acggactcgg 960gagcttggtc cggttgcacc tggatcacaa caacattgaa ttcatcaacc ctgaggcctt 1020ttatggactt acctcgctcc gcttggtaca tttagaagga aaccggctca caaagctcca 1080tccagacaca tttgtctcat taagctatct ccagatattt aaaacctctt tcattaagta 1140cctgttcttg tctgataact tcctgacctc cctcccaaaa gaaatggtct cctacatgcc 1200aaacctagaa agcctgtatt tgcatggaaa cccatggacc tgtgactgcc atttaaagtg 1260gttgtctgag tggatgcagg gaaacccaga tataataaaa tgcaagaaag acagaagctc 1320ttccagtcct cagcaatgtc ccctttgcat gaaccccagg atctctaaag gcagaccctt 1380tgctatggta ccatctggag ctttcctatg tacaaagcca accattgatc catcactgaa 1440gtcaaagagc ctggttactc aggaggacaa tggatctgcc tccacctcac ctcaagattt 1500catagaaccc tttggctcct tgtctttgaa catgacanan ntntctggaa ataaggccga 1560catggtctgt agtatccaaa agccatcaag gacatcacca actgcattca ctgaagaaaa 1620tgactacatc atgctaaatg cgtcattttc cacaaatctt gtgtgcagtg tagattataa 1680tcacatccag ccagtgtggc aacttctggc tttatacagt gactctcctc tgatactaga 1740aaggaagccc cagcttaccg agactccttc actgtcttct agatataaac aggtggctct 1800taggcctgaa gacattttta ccagcataga ggctgatgtc agagcagacc ctttttggtt 1860ccaacaagaa aaaattgtct tgcagctgaa cagaactgcc accacactta gcacattaca 1920gatccagttt tccactgatg ctcaaatcgc tttaccaagg gcggagatga gagcggagag 1980actcaaatgg accatgatcc tgatgatgaa caatcccaaa ctggaacgca ctgtcctggt 2040tggcggcact attgccctga gctgtccagg caaaggcgac ccttcacctc acttggaatg 2100gcttctagct gatgggagta aagtgagagc cccttacgtt agcgaggatg ggcgaatcct 2160aatagacaaa aatgggaagt tggaactgca gatggctgac agctttgatg caggtcttta 2220ccactgcata agcaccaatg atgcagatgc ggatgttctc acatacagga taactgtggt 2280agagccctat ggagaaagca cacatgacag tggagtccag cacacagtgg ttacgggtga 2340gacgctcgac cttccatgcc tttccacggg tgttccagat gcttctatta gctggattct 2400tccagggaac actgtgttct ctcagccatc aagagacagg caaattctta acaatgggac 2460cttaagaata ttacaggtta cgccaaaaga tcaaggtcat taccaatgtg tggctgccaa 2520cccatcaggg gccgactttt ccagttttaa agtttcagtt caaaagaaag gccaaaggat 2580ggttgagcat gacagggagg caggtggatc tggacttgga gaacccaact ccagtgtttc 2640ccttaagcag ccagcatctt tgaaactctc tgcatcagct ttgacagggt cagaggctgg 2700aaaacaagtc tccggtgtac ataggaagaa caaacataga gacttaatac atcggcggcg 2760tggggattcc acgctccggc gattcaggga gcataggagg cagctccctc tctctgctcg 2820gagaattgac ccgcaacgct gggcagcact tctagaaaaa gccaaaaaga attctgtgcc 2880aaaaaagcaa gaaaatacca cagtaaagcc agtgccactg gctgttcccc tcgtggaact 2940cactgacgag gaaaaggatg cctctggcat gattcctcca gatgaagaat tcatggttct 3000gaaaactaag gcttctggtg tcccaggaag gtcaccaact gctgactctg gaccagtaaa 3060tcatggtttt atgacgagta tagcttctgg cacagaagtc tcaactgtga atccacaaac 3120actacaatct gagcaccttc ctgatttcaa attatttagt gtaacaaacg gtacagctgt 3180gacaaagagt atgaacccat ccatagcaag caaaatagaa gatacaacca accaaaaccc 3240aatcattatc tttccatcag tagctgaaat tcgagattct gctcaggcag gaagagcatc 3300ttcccaaagt gcacaccctg taacaggggg aaacatggct acctatggcc ataccaacac 3360atatagtagc tttaccagca aagccagtac agtcttgcag ccaataaatc caacagaaag 3420ttatggacct cagataccta ttacaggagt cagcagacct agcagtagtg acatctcttc 3480tcacactact gcagacccta gcttctccag tcacccttca ggttcacaca ccactgcctc 3540gtctttattt cacattccta gaaacaacaa tacaggtaac ttccccttgt ccaggcactt 3600gggaagagag aggacaattt ggagcagagg gagagttaaa aacccacata gaaccccagt 3660tctccgacgg catagacaca ggactgtgag gccagcaatc aagggacctg ctaacaaaaa 3720tgtgagccaa gttccagcca cagagtaccc tgggatgtgc cacacatgtc cttccgcaga 3780ggggctcaca gtggctactg cagcactgtc agttccaagt tcatcccaca gtgccctccc 3840caaaactaat aatgttgggg tcatagcaga agagtctacc actgtggtca agaaaccact 3900gttactattt aaggacaaac aaaatgtaga tattgagata ataacaacca ctacaaaata 3960ttccggaggg gaaagtaacc acgtgattcc tacggaagca agcatgactt ctgctccaac 4020atctgtatcc ctggggaaat ctcctgtaga caatagtggt cacctgagca tgcctgggac 4080catccaaact gggaaagatt cagtggaaac aacaccactt cccagccccc tcagcacacc 4140ctcaatacca acaagcacaa aattctcaaa gaggaaaact cccttgcacc agatctttgt 4200aaataaccag aagaaggagg ggatgttaaa gaatccatat caattcggtt tacaaaagaa 4260cccagccgca aagcttccca aaatagctcc tcttttaccc acaggtcaga gttccccctc 4320agattctaca actctcttga caagtccgcc accagctctg tctacaacaa tggctgccac 4380tcagaacaag ggcactgaag tagtatcagg tgccagaagt ctctcagcag ggaagaagca 4440gcccttcacc aactcctctc cagtgcttcc tagcaccata agcaagagat ctaatacatt 4500aaacttcttg tcaacggaaa cccccacagt gacaagtcct actgctactg catctgtcat 4560tatgtctgaa acccaacgaa caagatccaa agaagcaaaa gaccaaataa aggggcctcg 4620gaagaacaga aacaacgcaa acaccacccc caggcaggtt tctggctata gtgcatactc 4680agctctaaca acagctgata cccccttggc tttcagtcat tccccacgac aagatgatgg 4740tggaaatgta agtgcagttg cttatcactc aacaacctct cttctggcca taactgaact 4800gtttgagaag tacacccaga ctttgggaaa tacaacagct ttggaaacaa cgttgttgag 4860caaatcacag gagagtacca cagtgaaaag agcctcagac acaccaccac cactcctcag 4920cagtggggcg cccccagtgc ccactccttc cccacctcct tttactaagg gtgtggttac 4980agacagcaaa gtcacatcag ctttccagat gacgtcaaat agagtggtca ccatatatga 5040atcttcaagg cacaatacag atctgcagca accctcagca gaggctagcc ccaatcctga 5100gatcataact ggaaccactg actctccctc taatctgttt ccatccactt ctgtgccagc 5160actaagggta gataaaccac agaattctaa atggaagccc tctccctggc cagaacacaa 5220atatcagctc aagtcatact ccgaaaccat tgagaagggc aaaaggccag cagtaagcat 5280gtccccccac ctcagccttc cagaggccag cactcatgcc tcacactgga atacacagaa 5340gcatgcagaa aagagtgttt ttgataagaa acctggtcaa aacccaactt ccaaacatct 5400gccttacgtc tctctaccta agactctatt gaaaaagcca agaataattg gaggaaaggc 5460tgcaagcttt acagttccag ctaattcaga cgtttttctt ccttgtgagg ctgttggaga 5520cccactgccc atcatccact ggaccagagt ttcatcagga nttgaaatat cccaagggac 5580acagaaaagc cggttccacg tgcttcccaa tggcaccttg tccatccaga gggtcagtat 5640tcaggaccgt ggacagtacc tgtgctctgc atttaatcca ctgggcgtag accattttca 5700tgtctctttg tctgtggttt tttacccggc aaggattttg gacagacatg tcaaggagat 5760cacagttcac tttggaagta ctgtggaact aaagtgcaga gtggagggta tgccgaggcc 5820tacggtttcc tggatacttg caaaccaaac ggtggtctca gaaacggcca agggaagcag 5880aaaggtctgg gtaacacctg atggaacatt gatcatctat aatctgagtc tttatgatcg 5940tggtttttac aagtgtgtgg ccagcaaccc atctggccag gattcactgt tggttaagat 6000acaagtcatc acagctcccc ctgtcattat agagcaaaag aggcaagcca tcgttggggt 6060tttaggtgga agtttgaaac tgccctgcac tgcaaaagga actccccagc ctagtgttca 6120ctgggtcctt tatgatggga ctgaactaaa accattgcag ttgactcatt ccagattttt 6180cttgtatcca aatggaactc tgtatataag aagcatcgct ccttcagtga ggggcactta 6240tgagtgcatt gccaccagct cctcaggctc agagagaagg gtagtgattc ttactgtgga 6300agagggagag acaatcccca ggatagaaac tgcctctcag aaatggactg aggtgaattt 6360gggtgagaaa ttactactga actgctcagc tactggggat ccaaagccta gaataatctg 6420gaggctgcca tccaaggctg tcatcgacca gtggcacaga atgggcagcc gaatccacgt 6480ctacccaaat ggatccttgg tggttgggtc agtgacggaa aaagacgctg gtgactactt 6540atgtgtggca agaaacaaaa tgggagatga cctagtcctg atgcatgtcc gcctgagatt 6600gacacctgcc aaaattgaac agaagcagta ttttaagaag caagtgctcc atgggaaaga 6660tttccaagtt gactgcaagg cctctggctc ccctgtgcct gaggtatcct ggagtttgcc 6720tgatgggaca gtgctcaaca atgtagccca agctgatgac agtggctata ggaccaagag 6780gtacaccctt ttccacaatg gaaccttgta tttcaacaac gttgggatgg cagaggaagg 6840agattatatc tgctctgccc agaacacctt agggaaagat gagatgaaag tccacctaac 6900agttctaaca gccatcccac ggataaggca aagctacaag accaccatga ggctcagggc 6960tggagaaaca gctgtccttg actgcgaggt cactggggaa ccgaagccca atgtattttg 7020gttgctgcct tccaacaatg tcatttcatt ctccaatgac aggttcacat ttcatgccaa 7080tagaactttg tccatccata aagtgaaacc acttgactct ggggactatg tgtgcgtagc 7140tcagaatcct agtggggatg acactaagac atacaaactg gacattgtct ctaaacctcc 7200attaatcaat ggcctgtatg caaacaagac tgttattaaa gccacagcca ttcggcactc 7260caaaaaatac tttgactgca gagcagatgg gatcccatct tcccaggtca cgtggattat 7320gccaggcaat attttcctcc cagctccata ctttggaagc agagtcacgg tccatccaaa 7380tggaaccttg gagatgagga acatccggct ttctgactct gcggacttca cctgtgtggt 7440tcggagcgag ggaggagaga gtgtgttggt agtgcagtta gaagtcctag aaatgctgag 7500aagaccaaca ttcagaaacc cattcaacga aaaagtcatc gcccaagctg gcaagcccgt 7560agcactgaac tgctctgtgg atgggaaccc cccacctgaa attacctgga tcttacctga 7620cggcacacag tttgctaaca gaccacacaa ttccccgtat ctgatggcag gcaatggctc 7680tctcatcctt tacaaagcaa ctcggaacaa gtcagggaag tatcgctgtg cagccaggaa 7740taaggttggc tacatcgaga aactcatcct gttagagatt gggcagaagc cagtcattct 7800gacatacgaa ccagggatgg tgaagagcgt cagtggggaa ccgttatcac tgcattgtgt 7860gtctgatggg atccccaagc caaatgtcaa gtggactaca ccgggtggcc atgtaatcga 7920caggcctcaa gtggatggaa aatacatact gcatgaaaat ggcacgctgg tcatcaaagc 7980aacaacagct cacgaccaag gaaattatat ctgtagggct caaaacagtg ttggccaggc 8040agttattagc gtgtcagtga tggttgtggc ctaccctccc cgaatcataa actacctacc 8100caggaacatg ctcaggagga caggggaagc catgcagctc cactgtgtgg ccttgggaat 8160ccccaagcca aaagtcacct gggagacgcc aagacactcc ctgctctcaa aagcaacagc 8220aagaaaaccc catagaagtg agatgcttca cccacaaggt acgctggtca ttcagaatct 8280ccaaacctcg gattccggag tctataagtg cagagctcag aacctacttg ggactgatta 8340cgcaacaact tacatccagg tactctgaca ggaaggggga gactaaaatt caacagaagt 8400ccacatccac agggtttatt ttttggaaga agtttaatca aaggcagcca taggcatgta 8460aatgagtctg aatacattta cagtattaaa tttacaatgg acatgcgatg agacttgtaa 8520atgaaagcat tgtgaactga aaccgagtct ctgtggatct caaagcaaac tcttaactta 8580aggcactttg attttgccaa caaataataa caaacattaa gagaaaaaaa tgatccacta 8640cgaaataaca aacggctaat gcacctgaat tctcagtaaa aagacctttc tctcgctaac 8700agttgccagc tgcctcgtgt ctgtttccta ccaatgtcac aaacatcgca cacagggtga 8760atggagtcaa cgggaaagat taagtttgcg gtctgtgtaa atctcaatgt acaaatattc 8820tgtcnctggt ttataaacat tttgataaaa ccgaaaaaaa aaaaaaaaaa aaaaaaaaaa 8880aaa 8883 8 8180 DNA homo sapiens misc_feature (1)..(8180) ′n′ can be anynucleotide ′a′, ′c′, ′g′ or ′t′. 8 tcacctgctt gctggtctcc tttgctgtgatctgcctggt cgccacccct gggggcaagg 60 cctgtcctcg ccgctgtgcc tgttatatgcctacggaggt acactgcaca tttcggtacc 120 tgacttccat cccagacagc atcccgcccaatgtggaacg catcaattta ggatacaaca 180 gcttggttag attgatggaa acagatttttctggcctgac caaactggag ttactcatgc 240 ttcacagcaa tggcattcac acaatccctgacaagacctt ctcagatttg caggccttgc 300 aggtcttaaa aatgagctat aataaagtccgaaaacttca gaaagatact ttttatggcc 360 tcaggagctt gacacgattg cacatggaccacaacaatat tgagtttata aacccagagg 420 ttttttatgg gctcaacttt ctccgcctggtgcacttgga aggaaatcag ctcactaagc 480 tccacccaga tacatttgtc tctttgagctacctccagat atttaaaatc tctttcatta 540 agttcctata cttgtctgat aacttcctgacctccctccc tcaagagatg gtctcctata 600 tgcctgacct agacagcctt tacctgcatggaaacccatg gacctgtgat tgccatttaa 660 agtggttgtc tgactggata caggnnnnnccagatgtaat aaaatgcaaa aaagatagaa 720 gtccctctag tgctcagcag tgtccactttgcatgaaccc taggacttct aaaggcaagc 780 cgttagctat ggtctcagct gcagctttccagtgtgccaa gccaaccatt gactcatccc 840 tgaaatcaaa gagcctgact attctggaagacagtagttc tgctttcatc tctccccaag 900 gtttcatggc accctttggc tccctcactttgaatatgac agatcagtct ggaaatgaag 960 ctaacatggt ctgcagtatt caaaagccctcaaggacatc acccattgca ttcactgaag 1020 aaaatgacta catcgtgcta aatacttcattttcaacatt tttggtgtgc aacatagatt 1080 acggtcacat tcagccagtg tggcaaattttggctttgta cagtgattct cctctgatac 1140 tagaaaggag ccacttgctt agtgaaacaccgcagctcta ttacaaatat aaacaggctt 1200 ggttaatgca agaccaaatt tccttgcagctgaacagaac tgccaccaca ttcagtacat 1260 tacagatcca gtactccagt gatgctcaaatcactttacc aagagcagag atgaggccag 1320 tgaaacacaa atggactatg atttcaagggataacaatac taagctggaa catactgtct 1380 tggtaggtgg aaccgttggc ctgaactgcccaggccaagg agaccccacc ccacacgtgg 1440 attggcttct agctgatgga agtaaagtgagagcccctta tgtcagtgag gatggacgga 1500 tcctaataga caaaagtgga aaattggaactccagatggc tgatagtttt gacacaggcg 1560 tatatcactg tataagcagc aattatgatgatgcagatat tctcacctat aggataactg 1620 tggtagaacc tttggtcgaa gcctatcaggaaaatgggat tcatcacaca gttttcattg 1680 gtgaaacact tgatcttcca tgccattctactggtatccc agatgcctct attagctggg 1740 ttattccagg aaacaatgtg ctctatcagtcatcaagaga caagaaagtt ctaaacaatg 1800 gcacattaag aatattacag gtcaccccgaaagaccaagg ttattatcgc tgtgtggcag 1860 ccaacccatc aggggttgat tttttgattttccaagtttc agtcaagatg aaaggacaaa 1920 ggcccttgga gcatgatgga gaaacagagggatctggact tgatgagtcc aatcctattg 1980 ctcatcttaa ggagccacca ggtgcacaactccgtacatc tgctctgatg gaggctgagg 2040 ttggaaaaca cacctcaagc acaagtaagaggcacaacta tcgggaatta acactccagc 2100 gacgtggaga ttcaacacat cgacgttttagggagaatag gaggcatttc cctccctctg 2160 ctaggagaat tgacccacaa cattgggcggcactgttgga gaaagctaaa aagaatgcta 2220 tgccagacaa gcgagaaaat accacagtgagcccaccccc agtggtcacc caactcccaa 2280 acatacctgg tgaagaagac gattcctcaggcatgctcgc tctacatgag gaatttatgg 2340 tcccggccac taaagctttg aaccttccagcaaggacagt gactgctgac tccagaacaa 2400 tatctgatag tcctatgaca aacataaattatggcacaga actctccgtt gtgaattcac 2460 aaatactacc acctgaagaa cccacagatttcaaactgtc tactgctatt aaaactacag 2520 ccatgtcaaa gaatataaac ccaaccatgtcaagccaaat acaaggcaca accaatcaac 2580 attcatccac tgtctttcca ctgctacttggagcaactga atttcaggac tctgacagag 2640 ggaagaggaa gagagcattt ccagtaacccccaataacag taaggactat gatcaaagat 2700 gntcaatgtc aaanatgctt agtagcaccaccaacaaact attattagag tcagtaaata 2760 ccacaaatag tcatcagaca tctgtaagagaagtgagtga acccaggcac aatcacttct 2820 attctcacac tactcaaata cttagcacctccacgttccc ttcagatcca cacacagctg 2880 ctcattctca gtttccgatc cctagannnaatagtacagt taacatcccg ctgttcagac 2940 gctttgggag gcagaggaaa attggcggaagggggcggat tatcagccca tatagaactc 3000 cagttctgcg acggcataga tacagcattttcaggtcaac aaccagaggt tcttctgaaa 3060 aaagcactac tgcattctca gccacagtgctcaatgtgac atgtctgtcc tgtcttccca 3120 gggagaggct caccactgcc acagcagcattgtcttttcc aagtgctgct cccatcacct 3180 tccccaaagc tgacattgct agagtcccatcagaagagtc tacaactcta gtccagaatc 3240 cactattact acttgagaac aaacccagtgtagannnnga aannacaaca cccacaataa 3300 aatattcagg actngaaatt tcccaagtgactccaactgg tgcagtcatg acatatgctc 3360 caacatccat acccatggaa aaaactcacaaagtaaacgc cagttaccca cgtgtgtcta 3420 gcaccaatga agctaaaaga gattcagtgattacatcgtc actttcaggt gctatcacca 3480 agccaccaat gactattata gccattacaaggttttcaag aaggaaaatt ccctggcaac 3540 agaactttgt aaataaccat aacccaaaaggcagattaag gaatcaacat aaagttagtt 3600 tacaaaaaag cacagctgtg atgcttcctaaaacatctcc tgctttacca cagagacaaa 3660 gttccccttt ccatttcacc acactttcaacaagtgtgat gcaaattcca tctaatacct 3720 tgactaccgc tcaccacact acgaccaaaacacacaatcc tggaagtctt ccaacaaaga 3780 aggagcttcc cttcccaccc cttaaccctatgcttcctag tattataagc aaagactcaa 3840 gtacaaaaag catcatatca acgcaaacagcaaccgcaac aactcctacc ttccctgcat 3900 ctgtcatcac ttatgaaacc caaacagagagatctagagc acaaacaata caaagagaag 3960 gacctcaaaa gaagaacagg actgacccaaacatctctcc agaccagagt tctggcttca 4020 ctacacccac tgctatgacn acctcctnngctctnnnngc attcactcat tccccaccag 4080 aaaacacaac tgggatttca agcacaatcagttttcattc aagaactctt aatctgacag 4140 atgtgattga agaactagcc caagcaagtactcagacttt gaagagcaca attgcttctg 4200 aaacaacttt gtccagcaaa tcacaccagagtaccacaac taggaaagca tcattagaca 4260 ctcaaccacc accattcttg agcagcagtgctactctaat gccagttccc atctcccctc 4320 cctttactca gagagcagtt actgacaacgtggcgactcc catttccggg cttatgacaa 4380 atacagtggt caagctgcac gaatcctcaaggcacaatcc nnnnnnncaa atgccaagtt 4440 cacnnaattg ngaaccnnnn actcnnnnnacttcatctac ntctaatctg ttacattcta 4500 ctcccatgcc agcactaaca acagttaaatcacagaattc caaattaact ccatctccct 4560 gggcagaata ccaattttgg cacaaaccatactcagacat tgctgaaaaa ggcaaaaagc 4620 cagaagtaag catgttggct actacaggcctgtccgaggc caccactctt gtttcagatt 4680 gggatggaca gaagaacaca aagaagagtgactttgataa gaaaccagtt caagaagcaa 4740 caacttccaa actccttccc tttgactctttgtctaggta tatatttgaa aagcccagga 4800 tagttggagg aaaagctgca agttttactattccagctaa ctcagatgcc tttcttccct 4860 gtgaagctgt tggaaatccc ctgcccaccattcattggac cagagtnnnn tcaggacttg 4920 atttatctaa gaggaaacag aatagcagggtccaggttct ccccaatggt accctgtcca 4980 tccagagggt ggaaattcag gaccgcggacagtacttgtg ttccgcatcc aatctgtttg 5040 gcacagacca ccttcatgtc accttgtctgtggtttccta tcctcccagg atcctggaga 5100 gacgtaccaa agagatcaca gttcattccggaagcactgt ggaactgaag tgcagagcag 5160 aaggtaggcc aagccctaca gttacctggattcttgcaaa ccaaacagtt gtctcagaat 5220 catcccaggg aagtaggcag gctgtggtgacggttgacgg aacattggtc ctccacaatc 5280 tcagtattta tgaccgtggc ttttacaaatgtgtggccag caacccaggt ggccaggatt 5340 cactgctggt taaaatacaa gtcattgcagcaccacctgt tattctagag caaaggaggc 5400 aagtcattgt aggcacttgg ggtgaaagtttaaaactgcc ctgtactgca aaaggaactc 5460 ctcagcccag cgtttactgg gtcctctctgatggcactga agtgaaacca ttacagttta 5520 ccaattccaa gttgttctta ttttcaaatgggactttgta tataagaaac ctagcctctt 5580 cagacagggg cacttatgaa tgcattgctaccagttccac tggttcggag cgaagagtag 5640 taatgcttac aatggaagag cgagtgaccagccccaggat agaagctgca tcccagaaaa 5700 ggactgaagt gaattttggg gacaaattactactgaactg ctcagccact ggggagccca 5760 aaccccaaat aatgtggagg ttaccatccaaggctgtggt cgaccagtgg gcagctggat 5820 ccacgtctac cctaatggat ccctgtttattggatcagta acagaaaaag acagtggtgt 5880 ctacttgtgt gtggcaagaa acaaaatgggggatgatctg atactgatgc atgttagcct 5940 aagactgaaa cctgccaaaa ttgaccacaagcagtatttt agaaagcaag tgctccatgg 6000 gaaagatttc caagtagatt gcaaagcttccggctcccca gtgccagaga tatcttggag 6060 tttgcctgat ggaaccatga tcaacaatgcaatgcaagcc gatgacagtg gccacaggac 6120 taggagatat acccttttca acaatggaactttatacttc aacaaagttg gggtagcgga 6180 ggaaggagat tatacttgct atgcccagaacaccctaggg aaagatgaaa tgaaggtcca 6240 cttaacagtt ataacagctg ctccccggataaggcagagt aacaaaacca acaagagaat 6300 caaagctgga gacacagctg tccttgactgtgaggtcact ggggatccca aaccaaaaat 6360 attttggttg ctgccttcca atgacatgatttccttctcc attgataggt acacatttca 6420 tgccaatggg tctttgacca tcaacaaagtgaaactgctc gattctggag agtacgtatg 6480 tgtagcccga aatcccagtg gggatgacaccaaaatgtac aaactggatg tggtctctaa 6540 acctccatta atcaatggtc tgtatacaaacagaactgtt attaaagcca cagctgtgag 6600 acattccaaa aaacactttg actgcagagctgaagggaca ccatctcctg aagtcatgtg 6660 gatcatgcca gacaatattt tcctcacagccccatactat ggaagcagaa tcacagtcca 6720 taaaaatgga accttggaaa ttaggaatgtgaggctttca gattcagccg actttatctg 6780 tgtggcccga aatgaaggtg gagagagcgtgttggtagta cagttagaag tactggaaat 6840 gctgagaaga ccgacattta gaaatccatttaatgaaaaa atagttgccc agctgggaaa 6900 gtccacagca ttgaattgct ctgttgatggtaacccacca cctgaaataa tctggatttt 6960 accaaatggc acacgatttt ccaatggaccacaaagttat cagtatctga tagcaagcaa 7020 tggttctttt atcatttcta aaacaactcgggaggatgca ggaaaatatc gctgtgcagc 7080 taggaataaa gttggctata ttgagaaattagtcatatta gaaattggcc agaagccagt 7140 tattcttacc tatgcaccag ggacagtaaaaggcatcagt ggagaatctc tatcactgca 7200 ttgtgtgtct gatggaatcc ctaagccaaatatcaaatgg actatgccaa gtggttatgt 7260 agtagacagg cctcaaatta atgggaaatacatattgcat gacaatggca ccttagtcat 7320 taaagaagca acagcttatg acagaggaaactatatctgt aaggctcaaa atagtgttgg 7380 tcatacactg attactgttc cagtaatgattgtagcctac cctccccgaa ttacaaatcg 7440 tccacccagg agtattgtca ccaggacaggggcagccttt cagctccact gtgtggcctt 7500 gggagttccc aagccagaaa tcacatgggagatgcctgac cactcccttc tctcaacggc 7560 aagtaaagag aggacacatg gaagtgagcagcttcactta caaggtaccc tagtcattca 7620 gaatccccaa acctccgatt ctgggatatacaaatgcaca gcaaagaacc cacttggtag 7680 tgattatgca gcaacgtata ttcaagtaatctgacatgaa ataataaagt caacaacatc 7740 tgggcagaat ttattttttg gaagaagtttaatcaaaggc agccataggc atgtaaatga 7800 atttgaatac atttacagta ttaaatttacaatgaacatg caaaataaaa ggacttgtaa 7860 ataaatgcat tatgaactga tgatactgatttatttaatg gatctcaaaa caaactttta 7920 acttaaggca cttttatttt gccaacaaataacaataaac aaacattgaa acggttcact 7980 ataaaataac aaatggctaa tgtacctgaatttttcagta aaaaaatgaa cttctaatac 8040 cagttgccta gtgtccacct cctatcaatgttacaagcat ggcactcaga acagagacaa 8100 tggaaaatat taaatctgca atctatgtataaatattttg tggtttataa atttttttgc 8160 taaaacctac agaaaataag 8180 9 897DNA Mus musculus misc_feature (1)..(897) ′n′ can be any nucleotide ′a′,′c′, ′g′ or ′t′. 9 aagaacgttc cttcaatcag gtgaaggctc tcctcagaagatttcctgtc tctgcttatg 60 tcagctgctt gctgatctcc ctcactgcca tctgcctggtggtcacccct gggagcaggg 120 tctgtcctcg ccgatgtgcc tgctatgtgc ccacagaggtgcactgtaca tttcgggacc 180 tgacctccat cccagacggg catcccagcc aatgtggaacgagtcaattt agggtataac 240 agcctcacta gattgacaga aaatgacttt tctggcctgagcagactgga gttactcatg 300 ctgcacagca atggcattca cagagtcagt gacaagaccttctcgggctt gcagtccttg 360 caggtcttaa aaatgagcta taacaaagtc caaataattgagaaggatac tttgtatgga 420 ctcaggagct tgacccggtt gcacctggat cacaacaacattgagtttat caaccccgag 480 gcgttttacg gactcacctt gctccgcttg gtacatctagaaggaaaccg gctgacaaag 540 ctccatccag acacatttgt ctctttgagc tatctccagatatttaaaac ctccttcatt 600 aagnacctgt acttgtatga taacttcatt gacctccctcccaaaagaaa tggtctcctc 660 tatgccaaac ctagaaagcc tttacttgca tggaaacccatggacctgtg actgccattt 720 aaagtggttg tccgagtgga tgcagggaaa cccaggtaactatcttgttt gtttgtttct 780 ttttttatar kacgtatttt cctcaatttc atttagaatgatatcccaaa agtcccccat 840 aacctccccc ccacttccct acctacccat tcccattttttggccctggc attcccc 897 10 2597 PRT Rattus sp. misc_feature (1)..(2597)′x′ can be any amino acid 10 Met Gln Val Arg Gly Arg Glu Val Ser Gly LeuLeu Ile Ser Leu Thr 1 5 10 15 Ala Val Cys Leu Val Val Thr Pro Gly SerArg Ala Cys Pro Arg Arg 20 25 30 Cys Ala Cys Tyr Val Pro Thr Glu Val HisCys Thr Phe Arg Tyr Leu 35 40 45 Thr Ser Ile Pro Asp Gly Ile Pro Ala AsnVal Glu Arg Ile Asn Leu 50 55 60 Gly Tyr Asn Ser Leu Thr Arg Leu Thr GluAsn Asp Phe Asp Gly Leu 65 70 75 80 Ser Lys Leu Glu Leu Leu Met Leu HisSer Asn Gly Ile His Arg Val 85 90 95 Ser Asp Lys Thr Phe Ser Gly Leu GlnSer Leu Gln Val Leu Lys Met 100 105 110 Ser Tyr Asn Lys Val Gln Ile IleArg Lys Asp Thr Phe Tyr Gly Leu 115 120 125 Gly Ser Leu Val Arg Leu HisLeu Asp His Asn Asn Ile Glu Phe Ile 130 135 140 Asn Pro Glu Ala Phe TyrGly Leu Thr Ser Leu Arg Leu Val His Leu 145 150 155 160 Glu Gly Asn ArgLeu Thr Lys Leu His Pro Asp Thr Phe Val Ser Leu 165 170 175 Ser Tyr LeuGln Ile Phe Lys Thr Ser Phe Ile Lys Tyr Leu Phe Leu 180 185 190 Ser AspAsn Phe Leu Thr Ser Leu Pro Lys Glu Met Val Ser Tyr Met 195 200 205 ProAsn Leu Glu Ser Leu Tyr Leu His Gly Asn Pro Trp Thr Cys Asp 210 215 220Cys His Leu Lys Trp Leu Ser Glu Trp Met Gln Gly Asn Pro Asp Ile 225 230235 240 Ile Lys Cys Lys Lys Asp Arg Ser Ser Ser Ser Pro Gln Gln Cys Pro245 250 255 Leu Cys Met Asn Pro Arg Ile Ser Lys Gly Arg Pro Phe Ala MetVal 260 265 270 Pro Ser Gly Ala Phe Leu Cys Thr Lys Pro Thr Ile Asp ProSer Leu 275 280 285 Lys Ser Lys Ser Leu Val Thr Gln Glu Asp Asn Gly SerAla Ser Thr 290 295 300 Ser Pro Gln Asp Phe Ile Glu Pro Phe Gly Ser LeuSer Leu Asn Met 305 310 315 320 Thr Xaa Xaa Ser Gly Asn Lys Ala Asp MetVal Cys Ser Ile Gln Lys 325 330 335 Pro Ser Arg Thr Ser Pro Thr Ala PheThr Glu Glu Asn Asp Tyr Ile 340 345 350 Met Leu Asn Ala Ser Phe Ser ThrAsn Leu Val Cys Ser Val Asp Tyr 355 360 365 Asn His Ile Gln Pro Val TrpGln Leu Leu Ala Leu Tyr Ser Asp Ser 370 375 380 Pro Leu Ile Leu Glu ArgLys Pro Gln Leu Thr Glu Thr Pro Ser Leu 385 390 395 400 Ser Ser Arg TyrLys Gln Val Ala Leu Arg Pro Glu Asp Ile Phe Thr 405 410 415 Ser Ile GluAla Asp Val Arg Ala Asp Pro Phe Trp Phe Gln Gln Glu 420 425 430 Lys IleVal Leu Gln Leu Asn Arg Thr Ala Thr Thr Leu Ser Thr Leu 435 440 445 GlnIle Gln Phe Ser Thr Asp Ala Gln Ile Ala Leu Pro Arg Ala Glu 450 455 460Met Arg Ala Glu Arg Leu Lys Trp Thr Met Ile Leu Met Met Asn Asn 465 470475 480 Pro Lys Leu Glu Arg Thr Val Leu Val Gly Gly Thr Ile Ala Leu Ser485 490 495 Cys Pro Gly Lys Gly Asp Pro Ser Pro His Leu Glu Trp Leu LeuAla 500 505 510 Asp Gly Ser Lys Val Arg Ala Pro Tyr Val Ser Glu Asp GlyArg Ile 515 520 525 Leu Ile Asp Lys Asn Gly Lys Leu Glu Leu Gln Met AlaAsp Ser Phe 530 535 540 Asp Ala Gly Leu Tyr His Cys Ile Ser Thr Asn AspAla Asp Ala Asp 545 550 555 560 Val Leu Thr Tyr Arg Ile Thr Val Val GluPro Tyr Gly Glu Ser Thr 565 570 575 His Asp Ser Gly Val Gln His Thr ValVal Thr Gly Glu Thr Leu Asp 580 585 590 Leu Pro Cys Leu Ser Thr Gly ValPro Asp Ala Ser Ile Ser Trp Ile 595 600 605 Leu Pro Gly Asn Thr Val PheSer Gln Pro Ser Arg Asp Arg Gln Ile 610 615 620 Leu Asn Asn Gly Thr LeuArg Ile Leu Gln Val Thr Pro Lys Asp Gln 625 630 635 640 Gly His Tyr GlnCys Val Ala Ala Asn Pro Ser Gly Ala Asp Phe Ser 645 650 655 Ser Phe LysVal Ser Val Gln Lys Lys Gly Gln Arg Met Val Glu His 660 665 670 Asp ArgGlu Ala Gly Gly Ser Gly Leu Gly Glu Pro Asn Ser Ser Val 675 680 685 SerLeu Lys Gln Pro Ala Ser Leu Lys Leu Ser Ala Ser Ala Leu Thr 690 695 700Gly Ser Glu Ala Gly Lys Gln Val Ser Gly Val His Arg Lys Asn Lys 705 710715 720 His Arg Asp Leu Ile His Arg Arg Arg Gly Asp Ser Thr Leu Arg Arg725 730 735 Phe Arg Glu His Arg Arg Gln Leu Pro Leu Ser Ala Arg Arg IleAsp 740 745 750 Pro Gln Arg Trp Ala Ala Leu Leu Glu Lys Ala Lys Lys AsnSer Val 755 760 765 Pro Lys Lys Gln Glu Asn Thr Thr Val Lys Pro Val ProLeu Ala Val 770 775 780 Pro Leu Val Glu Leu Thr Asp Glu Glu Lys Asp AlaSer Gly Met Ile 785 790 795 800 Pro Pro Asp Glu Glu Phe Met Val Leu LysThr Lys Ala Ser Gly Val 805 810 815 Pro Gly Arg Ser Pro Thr Ala Asp SerGly Pro Val Asn His Gly Phe 820 825 830 Met Thr Ser Ile Ala Ser Gly ThrGlu Val Ser Thr Val Asn Pro Gln 835 840 845 Thr Leu Gln Ser Glu His LeuPro Asp Phe Lys Leu Phe Ser Val Thr 850 855 860 Asn Gly Thr Ala Val ThrLys Ser Met Asn Pro Ser Ile Ala Ser Lys 865 870 875 880 Ile Glu Asp ThrThr Asn Gln Asn Pro Ile Ile Ile Phe Pro Ser Val 885 890 895 Ala Glu IleArg Asp Ser Ala Gln Ala Gly Arg Ala Ser Ser Gln Ser 900 905 910 Ala HisPro Val Thr Gly Gly Asn Met Ala Thr Tyr Gly His Thr Asn 915 920 925 ThrTyr Ser Ser Phe Thr Ser Lys Ala Ser Thr Val Leu Gln Pro Ile 930 935 940Asn Pro Thr Glu Ser Tyr Gly Pro Gln Ile Pro Ile Thr Gly Val Ser 945 950955 960 Arg Pro Ser Ser Ser Asp Ile Ser Ser His Thr Thr Ala Asp Pro Ser965 970 975 Phe Ser Ser His Pro Ser Gly Ser His Thr Thr Ala Ser Ser LeuPhe 980 985 990 His Ile Pro Arg Asn Asn Asn Thr Gly Asn Phe Pro Leu SerArg His 995 1000 1005 Leu Gly Arg Glu Arg Thr Ile Trp Ser Arg Gly ArgVal Lys Asn 1010 1015 1020 Pro His Arg Thr Pro Val Leu Arg Arg His ArgHis Arg Thr Val 1025 1030 1035 Arg Pro Ala Ile Lys Gly Pro Ala Asn LysAsn Val Ser Gln Val 1040 1045 1050 Pro Ala Thr Glu Tyr Pro Gly Met CysHis Thr Cys Pro Ser Ala 1055 1060 1065 Glu Gly Leu Thr Val Ala Thr AlaAla Leu Ser Val Pro Ser Ser 1070 1075 1080 Ser His Ser Ala Leu Pro LysThr Asn Asn Val Gly Val Ile Ala 1085 1090 1095 Glu Glu Ser Thr Thr ValVal Lys Lys Pro Leu Leu Leu Phe Lys 1100 1105 1110 Asp Lys Gln Asn ValAsp Ile Glu Ile Ile Thr Thr Thr Thr Lys 1115 1120 1125 Tyr Ser Gly GlyGlu Ser Asn His Val Ile Pro Thr Glu Ala Ser 1130 1135 1140 Met Thr SerAla Pro Thr Ser Val Ser Leu Gly Lys Ser Pro Val 1145 1150 1155 Asp AsnSer Gly His Leu Ser Met Pro Gly Thr Ile Gln Thr Gly 1160 1165 1170 LysAsp Ser Val Glu Thr Thr Pro Leu Pro Ser Pro Leu Ser Thr 1175 1180 1185Pro Ser Ile Pro Thr Ser Thr Lys Phe Ser Lys Arg Lys Thr Pro 1190 11951200 Leu His Gln Ile Phe Val Asn Asn Gln Lys Lys Glu Gly Met Leu 12051210 1215 Lys Asn Pro Tyr Gln Phe Gly Leu Gln Lys Asn Pro Ala Ala Lys1220 1225 1230 Leu Pro Lys Ile Ala Pro Leu Leu Pro Thr Gly Gln Ser SerPro 1235 1240 1245 Ser Asp Ser Thr Thr Leu Leu Thr Ser Pro Pro Pro AlaLeu Ser 1250 1255 1260 Thr Thr Met Ala Ala Thr Gln Asn Lys Gly Thr GluVal Val Ser 1265 1270 1275 Gly Ala Arg Ser Leu Ser Ala Gly Lys Lys GlnPro Phe Thr Asn 1280 1285 1290 Ser Ser Pro Val Leu Pro Ser Thr Ile SerLys Arg Ser Asn Thr 1295 1300 1305 Leu Asn Phe Leu Ser Thr Glu Thr ProThr Val Thr Ser Pro Thr 1310 1315 1320 Ala Thr Ala Ser Val Ile Met SerGlu Thr Gln Arg Thr Arg Ser 1325 1330 1335 Lys Glu Ala Lys Asp Gln IleLys Gly Pro Arg Lys Asn Arg Asn 1340 1345 1350 Asn Ala Asn Thr Thr ProArg Gln Val Ser Gly Tyr Ser Ala Tyr 1355 1360 1365 Ser Ala Leu Thr ThrAla Asp Thr Pro Leu Ala Phe Ser His Ser 1370 1375 1380 Pro Arg Gln AspAsp Gly Gly Asn Val Ser Ala Val Ala Tyr His 1385 1390 1395 Ser Thr ThrSer Leu Leu Ala Ile Thr Glu Leu Phe Glu Lys Tyr 1400 1405 1410 Thr GlnThr Leu Gly Asn Thr Thr Ala Leu Glu Thr Thr Leu Leu 1415 1420 1425 SerLys Ser Gln Glu Ser Thr Thr Val Lys Arg Ala Ser Asp Thr 1430 1435 1440Pro Pro Pro Leu Leu Ser Ser Gly Ala Pro Pro Val Pro Thr Pro 1445 14501455 Ser Pro Pro Pro Phe Thr Lys Gly Val Val Thr Asp Ser Lys Val 14601465 1470 Thr Ser Ala Phe Gln Met Thr Ser Asn Arg Val Val Thr Ile Tyr1475 1480 1485 Glu Ser Ser Arg His Asn Thr Asp Leu Gln Gln Pro Ser AlaGlu 1490 1495 1500 Ala Ser Pro Asn Pro Glu Ile Ile Thr Gly Thr Thr AspSer Pro 1505 1510 1515 Ser Asn Leu Phe Pro Ser Thr Ser Val Pro Ala LeuArg Val Asp 1520 1525 1530 Lys Pro Gln Asn Ser Lys Trp Lys Pro Ser ProTrp Pro Glu His 1535 1540 1545 Lys Tyr Gln Leu Lys Ser Tyr Ser Glu ThrIle Glu Lys Gly Lys 1550 1555 1560 Arg Pro Ala Val Ser Met Ser Pro HisLeu Ser Leu Pro Glu Ala 1565 1570 1575 Ser Thr His Ala Ser His Trp AsnThr Gln Lys His Ala Glu Lys 1580 1585 1590 Ser Val Phe Asp Lys Lys ProGly Gln Asn Pro Thr Ser Lys His 1595 1600 1605 Leu Pro Tyr Val Ser LeuPro Lys Thr Leu Leu Lys Lys Pro Arg 1610 1615 1620 Ile Ile Gly Gly LysAla Ala Ser Phe Thr Val Pro Ala Asn Ser 1625 1630 1635 Asp Val Phe LeuPro Cys Glu Ala Val Gly Asp Pro Leu Pro Ile 1640 1645 1650 Ile His TrpThr Arg Val Ser Ser Gly Xaa Glu Ile Ser Gln Gly 1655 1660 1665 Thr GlnLys Ser Arg Phe His Val Leu Pro Asn Gly Thr Leu Ser 1670 1675 1680 IleGln Arg Val Ser Ile Gln Asp Arg Gly Gln Tyr Leu Cys Ser 1685 1690 1695Ala Phe Asn Pro Leu Gly Val Asp His Phe His Val Ser Leu Ser 1700 17051710 Val Val Phe Tyr Pro Ala Arg Ile Leu Asp Arg His Val Lys Glu 17151720 1725 Ile Thr Val His Phe Gly Ser Thr Val Glu Leu Lys Cys Arg Val1730 1735 1740 Glu Gly Met Pro Arg Pro Thr Val Ser Trp Ile Leu Ala AsnGln 1745 1750 1755 Thr Val Val Ser Glu Thr Ala Lys Gly Ser Arg Lys ValTrp Val 1760 1765 1770 Thr Pro Asp Gly Thr Leu Ile Ile Tyr Asn Leu SerLeu Tyr Asp 1775 1780 1785 Arg Gly Phe Tyr Lys Cys Val Ala Ser Asn ProSer Gly Gln Asp 1790 1795 1800 Ser Leu Leu Val Lys Ile Gln Val Ile ThrAla Pro Pro Val Ile 1805 1810 1815 Ile Glu Gln Lys Arg Gln Ala Ile ValGly Val Leu Gly Gly Ser 1820 1825 1830 Leu Lys Leu Pro Cys Thr Ala LysGly Thr Pro Gln Pro Ser Val 1835 1840 1845 His Trp Val Leu Tyr Asp GlyThr Glu Leu Lys Pro Leu Gln Leu 1850 1855 1860 Thr His Ser Arg Phe PheLeu Tyr Pro Asn Gly Thr Leu Tyr Ile 1865 1870 1875 Arg Ser Ile Ala ProSer Val Arg Gly Thr Tyr Glu Cys Ile Ala 1880 1885 1890 Thr Ser Ser SerGly Ser Glu Arg Arg Val Val Ile Leu Thr Val 1895 1900 1905 Glu Glu GlyGlu Thr Ile Pro Arg Ile Glu Thr Ala Ser Gln Lys 1910 1915 1920 Trp ThrGlu Val Asn Leu Gly Glu Lys Leu Leu Leu Asn Cys Ser 1925 1930 1935 AlaThr Gly Asp Pro Lys Pro Arg Ile Ile Trp Arg Leu Pro Ser 1940 1945 1950Lys Ala Val Ile Asp Gln Trp His Arg Met Gly Ser Arg Ile His 1955 19601965 Val Tyr Pro Asn Gly Ser Leu Val Val Gly Ser Val Thr Glu Lys 19701975 1980 Asp Ala Gly Asp Tyr Leu Cys Val Ala Arg Asn Lys Met Gly Asp1985 1990 1995 Asp Leu Val Leu Met His Val Arg Leu Arg Leu Thr Pro AlaLys 2000 2005 2010 Ile Glu Gln Lys Gln Tyr Phe Lys Lys Gln Val Leu HisGly Lys 2015 2020 2025 Asp Phe Gln Val Asp Cys Lys Ala Ser Gly Ser ProVal Pro Glu 2030 2035 2040 Val Ser Trp Ser Leu Pro Asp Gly Thr Val LeuAsn Asn Val Ala 2045 2050 2055 Gln Ala Asp Asp Ser Gly Tyr Arg Thr LysArg Tyr Thr Leu Phe 2060 2065 2070 His Asn Gly Thr Leu Tyr Phe Asn AsnVal Gly Met Ala Glu Glu 2075 2080 2085 Gly Asp Tyr Ile Cys Ser Ala GlnAsn Thr Leu Gly Lys Asp Glu 2090 2095 2100 Met Lys Val His Leu Thr ValLeu Thr Ala Ile Pro Arg Ile Arg 2105 2110 2115 Gln Ser Tyr Lys Thr ThrMet Arg Leu Arg Ala Gly Glu Thr Ala 2120 2125 2130 Val Leu Asp Cys GluVal Thr Gly Glu Pro Lys Pro Asn Val Phe 2135 2140 2145 Trp Leu Leu ProSer Asn Asn Val Ile Ser Phe Ser Asn Asp Arg 2150 2155 2160 Phe Thr PheHis Ala Asn Arg Thr Leu Ser Ile His Lys Val Lys 2165 2170 2175 Pro LeuAsp Ser Gly Asp Tyr Val Cys Val Ala Gln Asn Pro Ser 2180 2185 2190 GlyAsp Asp Thr Lys Thr Tyr Lys Leu Asp Ile Val Ser Lys Pro 2195 2200 2205Pro Leu Ile Asn Gly Leu Tyr Ala Asn Lys Thr Val Ile Lys Ala 2210 22152220 Thr Ala Ile Arg His Ser Lys Lys Tyr Phe Asp Cys Arg Ala Asp 22252230 2235 Gly Ile Pro Ser Ser Gln Val Thr Trp Ile Met Pro Gly Asn Ile2240 2245 2250 Phe Leu Pro Ala Pro Tyr Phe Gly Ser Arg Val Thr Val HisPro 2255 2260 2265 Asn Gly Thr Leu Glu Met Arg Asn Ile Arg Leu Ser AspSer Ala 2270 2275 2280 Asp Phe Thr Cys Val Val Arg Ser Glu Gly Gly GluSer Val Leu 2285 2290 2295 Val Val Gln Leu Glu Val Leu Glu Met Leu ArgArg Pro Thr Phe 2300 2305 2310 Arg Asn Pro Phe Asn Glu Lys Val Ile AlaGln Ala Gly Lys Pro 2315 2320 2325 Val Ala Leu Asn Cys Ser Val Asp GlyAsn Pro Pro Pro Glu Ile 2330 2335 2340 Thr Trp Ile Leu Pro Asp Gly ThrGln Phe Ala Asn Arg Pro His 2345 2350 2355 Asn Ser Pro Tyr Leu Met AlaGly Asn Gly Ser Leu Ile Leu Tyr 2360 2365 2370 Lys Ala Thr Arg Asn LysSer Gly Lys Tyr Arg Cys Ala Ala Arg 2375 2380 2385 Asn Lys Val Gly TyrIle Glu Lys Leu Ile Leu Leu Glu Ile Gly 2390 2395 2400 Gln Lys Pro ValIle Leu Thr Tyr Glu Pro Gly Met Val Lys Ser 2405 2410 2415 Val Ser GlyGlu Pro Leu Ser Leu His Cys Val Ser Asp Gly Ile 2420 2425 2430 Pro LysPro Asn Val Lys Trp Thr Thr Pro Gly Gly His Val Ile 2435 2440 2445 AspArg Pro Gln Val Asp Gly Lys Tyr Ile Leu His Glu Asn Gly 2450 2455 2460Thr Leu Val Ile Lys Ala Thr Thr Ala His Asp Gln Gly Asn Tyr 2465 24702475 Ile Cys Arg Ala Gln Asn Ser Val Gly Gln Ala Val Ile Ser Val 24802485 2490 Ser Val Met Val Val Ala Tyr Pro Pro Arg Ile Ile Asn Tyr Leu2495 2500 2505 Pro Arg Asn Met Leu Arg Arg Thr Gly Glu Ala Met Gln LeuHis 2510 2515 2520 Cys Val Ala Leu Gly Ile Pro Lys Pro Lys Val Thr TrpGlu Thr 2525 2530 2535 Pro Arg His Ser Leu Leu Ser Lys Ala Thr Ala ArgLys Pro His 2540 2545 2550 Arg Ser Glu Met Leu His Pro Gln Gly Thr LeuVal Ile Gln Asn 2555 2560 2565 Leu Gln Thr Ser Asp Ser Gly Val Tyr LysCys Arg Ala Gln Asn 2570 2575 2580 Leu Leu Gly Thr Asp Tyr Ala Thr ThrTyr Ile Gln Val Leu 2585 2590 2595 11 2586 PRT Homo sapiens misc_feature(1)..(2586) ′x′ can be any amino acid 11 Met Lys Val Lys Gly Arg Gly IleThr Cys Leu Leu Val Ser Phe Ala 1 5 10 15 Val Ile Cys Leu Val Ala ThrPro Gly Gly Lys Ala Cys Pro Arg Arg 20 25 30 Cys Ala Cys Tyr Met Pro ThrGlu Val His Cys Thr Phe Arg Tyr Leu 35 40 45 Thr Ser Ile Pro Asp Ser IlePro Pro Asn Val Glu Arg Ile Asn Leu 50 55 60 Gly Tyr Asn Ser Leu Val ArgLeu Met Glu Thr Asp Phe Ser Gly Leu 65 70 75 80 Thr Lys Leu Glu Leu LeuMet Leu His Ser Asn Gly Ile His Thr Ile 85 90 95 Pro Asp Lys Thr Phe SerAsp Leu Gln Ala Leu Gln Val Leu Lys Met 100 105 110 Ser Tyr Asn Lys ValArg Lys Leu Gln Lys Asp Thr Phe Tyr Gly Leu 115 120 125 Arg Ser Leu ThrArg Leu His Met Asp His Asn Asn Ile Glu Phe Ile 130 135 140 Asn Pro GluVal Phe Tyr Gly Leu Asn Phe Leu Arg Leu Val His Leu 145 150 155 160 GluGly Asn Gln Leu Thr Lys Leu His Pro Asp Thr Phe Val Ser Leu 165 170 175Ser Tyr Leu Gln Ile Phe Lys Ile Ser Phe Ile Lys Phe Leu Tyr Leu 180 185190 Ser Asp Asn Phe Leu Thr Ser Leu Pro Gln Glu Met Val Ser Tyr Met 195200 205 Pro Asp Leu Asp Ser Leu Tyr Leu His Gly Asn Pro Trp Thr Cys Asp210 215 220 Cys His Leu Lys Trp Leu Ser Asp Trp Ile Gln Pro Asp Val IleLys 225 230 235 240 Cys Lys Lys Asp Arg Ser Pro Ser Ser Ala Gln Gln CysPro Leu Cys 245 250 255 Met Asn Pro Arg Thr Ser Lys Gly Lys Pro Leu AlaMet Val Ser Ala 260 265 270 Ala Ala Phe Gln Cys Ala Lys Pro Thr Ile AspSer Ser Leu Lys Ser 275 280 285 Lys Ser Leu Thr Ile Leu Glu Asp Ser SerSer Ala Phe Ile Ser Pro 290 295 300 Gln Gly Phe Met Ala Pro Phe Gly SerLeu Thr Leu Asn Met Thr Asp 305 310 315 320 Gln Ser Gly Asn Glu Ala AsnMet Val Cys Ser Ile Gln Lys Pro Ser 325 330 335 Arg Thr Ser Pro Ile AlaPhe Thr Glu Glu Asn Asp Tyr Ile Val Leu 340 345 350 Asn Thr Ser Phe SerThr Phe Leu Val Cys Asn Ile Asp Tyr Gly His 355 360 365 Ile Gln Pro ValTrp Gln Ile Leu Ala Leu Tyr Ser Asp Ser Pro Leu 370 375 380 Ile Leu GluArg Ser His Leu Leu Ser Glu Thr Pro Gln Leu Tyr Tyr 385 390 395 400 LysTyr Lys Gln Val Ala Pro Lys Pro Glu Asp Ile Phe Thr Asn Ile 405 410 415Glu Ala Asp Leu Arg Ala Asp Pro Ser Trp Leu Met Gln Asp Gln Ile 420 425430 Ser Leu Gln Leu Asn Arg Thr Ala Thr Thr Phe Ser Thr Leu Gln Ile 435440 445 Gln Tyr Ser Ser Asp Ala Gln Ile Thr Leu Pro Arg Ala Glu Met Arg450 455 460 Pro Val Lys His Lys Trp Thr Met Ile Ser Arg Asp Asn Asn ThrLys 465 470 475 480 Leu Glu His Thr Val Leu Val Gly Gly Thr Val Gly LeuAsn Cys Pro 485 490 495 Gly Gln Gly Asp Pro Thr Pro His Val Asp Trp LeuLeu Ala Asp Gly 500 505 510 Ser Lys Val Arg Ala Pro Tyr Val Ser Glu AspGly Arg Ile Leu Ile 515 520 525 Asp Lys Ser Gly Lys Leu Glu Leu Gln MetAla Asp Ser Phe Asp Thr 530 535 540 Gly Val Tyr His Cys Ile Ser Ser AsnTyr Asp Asp Ala Asp Ile Leu 545 550 555 560 Thr Tyr Arg Ile Thr Val ValGlu Pro Leu Val Glu Ala Tyr Gln Glu 565 570 575 Asn Gly Ile His His ThrVal Phe Ile Gly Glu Thr Leu Asp Leu Pro 580 585 590 Cys His Ser Thr GlyIle Pro Asp Ala Ser Ile Ser Trp Val Ile Pro 595 600 605 Gly Asn Asn ValLeu Tyr Gln Ser Ser Arg Asp Lys Lys Val Leu Asn 610 615 620 Asn Gly ThrLeu Arg Ile Leu Gln Val Thr Pro Lys Asp Gln Gly Tyr 625 630 635 640 TyrArg Cys Val Ala Ala Asn Pro Ser Gly Val Asp Phe Leu Ile Phe 645 650 655Gln Val Ser Val Lys Met Lys Gly Gln Arg Pro Leu Glu His Asp Gly 660 665670 Glu Thr Glu Gly Ser Gly Leu Asp Glu Ser Asn Pro Ile Ala His Leu 675680 685 Lys Glu Pro Pro Gly Ala Gln Leu Arg Thr Ser Ala Leu Met Glu Ala690 695 700 Glu Val Gly Lys His Thr Ser Ser Thr Ser Lys Arg His Asn TyrArg 705 710 715 720 Glu Leu Thr Leu Gln Arg Arg Gly Asp Ser Thr His ArgArg Phe Arg 725 730 735 Glu Asn Arg Arg His Phe Pro Pro Ser Ala Arg ArgIle Asp Pro Gln 740 745 750 His Trp Ala Ala Leu Leu Glu Lys Ala Lys LysAsn Ala Met Pro Asp 755 760 765 Lys Arg Glu Asn Thr Thr Val Ser Pro ProPro Val Val Thr Gln Leu 770 775 780 Pro Asn Ile Pro Gly Glu Glu Asp AspSer Ser Gly Met Leu Ala Leu 785 790 795 800 His Glu Glu Phe Met Val ProAla Thr Lys Ala Leu Asn Leu Pro Ala 805 810 815 Arg Thr Val Thr Ala AspSer Arg Thr Ile Ser Asp Ser Pro Met Thr 820 825 830 Asn Ile Asn Tyr GlyThr Glu Phe Ser Pro Val Val Asn Ser Gln Ile 835 840 845 Leu Pro Pro GluGlu Pro Thr Asp Phe Lys Leu Ser Thr Ala Ile Lys 850 855 860 Thr Thr AlaMet Ser Lys Asn Ile Asn Pro Thr Met Ser Ser Gln Ile 865 870 875 880 GlnGly Thr Thr Asn Gln His Ser Ser Thr Val Phe Pro Leu Leu Leu 885 890 895Gly Ala Thr Glu Phe Gln Asp Ser Asp Gln Met Gly Arg Gly Arg Glu 900 905910 His Phe Gln Ser Arg Pro Pro Ile Thr Val Arg Thr Met Ile Lys Asp 915920 925 Val Asn Val Lys Met Leu Ser Ser Thr Thr Asn Lys Leu Leu Leu Glu930 935 940 Ser Val Asn Thr Thr Asn Ser His Gln Thr Ser Val Arg Glu ValSer 945 950 955 960 Glu Pro Arg His Asn His Phe Tyr Ser His Thr Thr GlnIle Leu Ser 965 970 975 Thr Ser Thr Phe Pro Ser Asp Pro His Thr Ala AlaHis Ser Gln Phe 980 985 990 Pro Ile Pro Arg Asn Ser Thr Val Asn Ile ProLeu Phe Arg Arg Phe 995 1000 1005 Gly Arg Gln Arg Lys Ile Gly Gly ArgGly Arg Ile Ile Ser Pro 1010 1015 1020 Tyr Arg Thr Pro Val Leu Arg ArgHis Arg Tyr Ser Ile Phe Arg 1025 1030 1035 Ser Thr Thr Arg Gly Ser SerGlu Lys Ser Thr Thr Ala Phe Ser 1040 1045 1050 Ala Thr Val Leu Asn ValThr Cys Leu Ser Cys Leu Pro Arg Glu 1055 1060 1065 Arg Leu Thr Thr AlaThr Ala Ala Leu Ser Phe Pro Ser Ala Ala 1070 1075 1080 Pro Ile Thr PhePro Lys Ala Asp Ile Ala Arg Val Pro Ser Glu 1085 1090 1095 Glu Ser ThrThr Leu Val Gln Asn Pro Leu Leu Leu Leu Glu Asn 1100 1105 1110 Lys ProSer Val Glu Lys Thr Thr Pro Thr Ile Lys Tyr Phe Arg 1115 1120 1125 ThrGlu Ile Ser Gln Val Thr Pro Thr Gly Ala Val Met Thr Tyr 1130 1135 1140Ala Pro Thr Ser Ile Pro Met Glu Lys Thr His Lys Val Asn Ala 1145 11501155 Ser Tyr Pro Arg Val Ser Ser Thr Asn Glu Ala Lys Arg Asp Ser 11601165 1170 Val Ile Thr Ser Ser Leu Ser Gly Ala Ile Thr Lys Pro Pro Met1175 1180 1185 Thr Ile Ile Ala Ile Thr Arg Phe Ser Arg Arg Lys Ile ProTrp 1190 1195 1200 Gln Gln Asn Phe Val Asn Asn His Asn Pro Lys Gly ArgLeu Arg 1205 1210 1215 Asn Gln His Lys Val Ser Leu Gln Lys Ser Thr AlaVal Met Leu 1220 1225 1230 Pro Lys Thr Ser Pro Ala Leu Pro Gln Arg GlnSer Ser Pro Phe 1235 1240 1245 His Phe Thr Thr Leu Ser Thr Ser Val MetGln Ile Pro Ser Asn 1250 1255 1260 Thr Leu Thr Thr Ala His His Thr ThrThr Lys Thr His Asn Pro 1265 1270 1275 Gly Ser Leu Pro Thr Lys Lys GluLeu Pro Phe Pro Pro Leu Asn 1280 1285 1290 Pro Met Leu Pro Ser Ile IleSer Lys Asp Ser Ser Thr Lys Ser 1295 1300 1305 Ile Ile Ser Thr Gln ThrAla Ile Pro Ala Thr Thr Pro Thr Phe 1310 1315 1320 Pro Ala Ser Val IleThr Tyr Glu Thr Gln Thr Glu Arg Ser Arg 1325 1330 1335 Ala Gln Thr IleGln Arg Glu Gln Glu Pro Gln Lys Lys Asn Arg 1340 1345 1350 Thr Asp ProAsn Ile Ser Pro Asp Gln Ser Ser Gly Phe Thr Thr 1355 1360 1365 Pro ThrAla Met Thr Pro Pro Ala Leu Ala Phe Thr His Ser Pro 1370 1375 1380 ProGlu Asn Thr Thr Gly Ile Ser Ser Thr Ile Ser Phe His Ser 1385 1390 1395Arg Thr Leu Asn Leu Thr Asp Val Ile Glu Glu Leu Ala Gln Ala 1400 14051410 Ser Thr Gln Thr Leu Lys Ser Thr Ile Ala Ser Glu Thr Thr Leu 14151420 1425 Ser Ser Lys Ser His Gln Ser Thr Thr Thr Arg Lys Ala Ser Leu1430 1435 1440 Asp Thr Pro Ile Pro Pro Phe Leu Ser Ser Ser Ala Thr LeuMet 1445 1450 1455 Pro Val Pro Ile Ser Pro Pro Phe Thr Gln Arg Ala ValThr Asp 1460 1465 1470 Thr Arg Gly Asp Ser His Phe Arg Leu Met Thr AsnThr Val Val 1475 1480 1485 Lys Leu His Glu Ser Ser Arg His Asn Leu GlnMet Pro Ser Ser 1490 1495 1500 Gln Leu Glu Pro Leu Thr Ser Ser Thr SerAsn Leu Leu His Ser 1505 1510 1515 Thr Pro Met Pro Ala Leu Thr Thr ValLys Ser Gln Asn Ser Lys 1520 1525 1530 Leu Thr Pro Ser Pro Trp Ala GluTyr Gln Phe Trp His Lys Pro 1535 1540 1545 Tyr Ser Asp Ile Ala Glu LysGly Lys Lys Pro Glu Val Ser Met 1550 1555 1560 Leu Ala Thr Thr Gly LeuSer Glu Ala Thr Thr Leu Val Ser Asp 1565 1570 1575 Trp Asp Gly Gln LysAsn Thr Lys Lys Ser Asp Phe Asp Lys Lys 1580 1585 1590 Pro Val Gln GluAla Thr Thr Ser Lys Leu Leu Pro Phe Asp Ser 1595 1600 1605 Leu Ser ArgTyr Ile Phe Glu Lys Pro Arg Ile Val Gly Gly Lys 1610 1615 1620 Ala AlaSer Phe Thr Ile Pro Ala Asn Ser Asp Ala Phe Leu Pro 1625 1630 1635 CysGlu Ala Val Gly Asn Pro Leu Pro Thr Ile His Trp Thr Arg 1640 1645 1650Val Ser Gly Leu Asp Leu Ser Arg Gly Asn Gln Asn Ser Arg Val 1655 16601665 Gln Val Leu Pro Asn Gly Thr Leu Ser Ile Gln Arg Val Glu Ile 16701675 1680 Gln Asp Arg Gly Gln Tyr Leu Cys Ser Ala Ser Asn Leu Phe Gly1685 1690 1695 Thr Asp His Leu His Val Thr Leu Ser Val Val Ser Tyr ProPro 1700 1705 1710 Arg Ile Leu Glu Arg Arg Thr Lys Glu Ile Thr Val HisSer Gly 1715 1720 1725 Ser Thr Val Glu Leu Lys Cys Arg Ala Glu Gly ArgPro Ser Pro 1730 1735 1740 Thr Val Thr Trp Ile Leu Ala Asn Gln Thr ValVal Ser Glu Ser 1745 1750 1755 Ser Gln Gly Ser Arg Gln Ala Val Val ThrVal Asp Gly Thr Leu 1760 1765 1770 Val Leu His Asn Leu Ser Ile Tyr AspArg Gly Phe Tyr Lys Cys 1775 1780 1785 Val Ala Ser Asn Pro Gly Gly GlnAsp Ser Leu Leu Val Lys Ile 1790 1795 1800 Gln Val Ile Ala Ala Pro ProVal Ile Leu Glu Gln Arg Arg Gln 1805 1810 1815 Val Ile Val Gly Thr TrpGly Glu Ser Leu Lys Leu Pro Cys Thr 1820 1825 1830 Ala Lys Gly Thr ProGln Pro Ser Val Tyr Trp Val Leu Ser Asp 1835 1840 1845 Gly Thr Glu ValLys Pro Leu Gln Phe Thr Asn Ser Lys Leu Phe 1850 1855 1860 Leu Phe SerAsn Gly Thr Leu Tyr Ile Arg Asn Leu Ala Ser Ser 1865 1870 1875 Asp ArgGly Thr Tyr Glu Cys Ile Ala Thr Ser Ser Thr Gly Ser 1880 1885 1890 GluArg Arg Val Val Met Leu Thr Met Glu Glu Arg Val Thr Ser 1895 1900 1905Pro Arg Ile Glu Ala Ala Ser Gln Lys Arg Thr Glu Val Asn Phe 1910 19151920 Gly Asp Lys Leu Leu Leu Asn Cys Ser Ala Thr Gly Glu Pro Lys 19251930 1935 Pro Gln Ile Met Trp Arg Leu Pro Ser Lys Ala Val Val Asp Gln1940 1945 1950 Gly Ser Trp Ile His Val Tyr Pro Asn Gly Ser Leu Phe IleGly 1955 1960 1965 Ser Val Thr Glu Lys Asp Ser Gly Val Tyr Leu Cys ValAla Arg 1970 1975 1980 Asn Lys Met Gly Asp Asp Leu Ile Leu Met His ValSer Leu Arg 1985 1990 1995 Leu Lys Pro Ala Lys Ile Asp His Lys Gln TyrPhe Arg Lys Gln 2000 2005 2010 Val Leu His Gly Lys Asp Phe Gln Val AspCys Lys Ala Ser Gly 2015 2020 2025 Ser Pro Val Pro Glu Ile Ser Trp SerLeu Pro Asp Gly Thr Met 2030 2035 2040 Ile Asn Asn Ala Met Gln Ala AspAsp Ser Gly His Arg Thr Arg 2045 2050 2055 Arg Tyr Thr Leu Phe Asn AsnGly Thr Leu Tyr Phe Asn Lys Val 2060 2065 2070 Gly Val Ala Glu Glu GlyAsp Tyr Thr Cys Tyr Ala Gln Asn Thr 2075 2080 2085 Leu Gly Lys Asp GluMet Lys Val His Leu Thr Val Ile Thr Ala 2090 2095 2100 Ala Pro Arg IleArg Gln Ser Asn Lys Thr Asn Lys Arg Ile Lys 2105 2110 2115 Ala Gly AspThr Ala Val Leu Asp Cys Glu Val Thr Gly Asp Pro 2120 2125 2130 Lys ProLys Ile Phe Trp Leu Leu Pro Ser Asn Asp Met Ile Ser 2135 2140 2145 PheSer Ile Asp Arg Tyr Thr Phe His Ala Asn Gly Ser Leu Thr 2150 2155 2160Ile Asn Lys Val Lys Leu Leu Asp Ser Gly Glu Tyr Val Cys Val 2165 21702175 Ala Arg Asn Pro Ser Gly Asp Asp Thr Lys Met Tyr Lys Leu Asp 21802185 2190 Val Val Ser Lys Pro Pro Leu Ile Asn Gly Leu Tyr Thr Asn Arg2195 2200 2205 Thr Val Ile Lys Ala Thr Ala Val Arg His Ser Lys Lys HisPhe 2210 2215 2220 Asp Cys Arg Ala Glu Gly Thr Pro Ser Pro Glu Val MetTrp Ile 2225 2230 2235 Met Pro Asp Asn Ile Phe Leu Thr Ala Pro Tyr TyrGly Ser Arg 2240 2245 2250 Ile Thr Val His Lys Asn Gly Thr Leu Glu IleArg Asn Val Arg 2255 2260 2265 Leu Ser Asp Ser Ala Asp Phe Ile Cys ValAla Arg Asn Glu Gly 2270 2275 2280 Gly Glu Ser Val Leu Val Val Gln LeuGlu Val Leu Glu Met Leu 2285 2290 2295 Arg Arg Pro Thr Phe Arg Asn ProPhe Asn Glu Lys Ile Val Ala 2300 2305 2310 Gln Leu Gly Lys Ser Thr AlaLeu Asn Cys Ser Val Asp Gly Asn 2315 2320 2325 Pro Pro Pro Glu Ile IleTrp Ile Leu Pro Asn Gly Thr Arg Phe 2330 2335 2340 Ser Asn Gly Pro GlnSer Tyr Gln Tyr Leu Ile Ala Ser Asn Gly 2345 2350 2355 Ser Phe Ile IleSer Lys Thr Thr Arg Glu Asp Ala Gly Lys Tyr 2360 2365 2370 Arg Cys AlaAla Arg Asn Lys Val Gly Tyr Ile Glu Lys Leu Val 2375 2380 2385 Ile LeuGlu Ile Gly Gln Lys Pro Val Ile Leu Thr Tyr Ala Pro 2390 2395 2400 GlyThr Val Lys Gly Ile Ser Gly Glu Ser Leu Ser Leu His Cys 2405 2410 2415Val Ser Asp Gly Ile Pro Lys Pro Asn Ile Lys Trp Thr Met Pro 2420 24252430 Ser Gly Tyr Val Val Asp Arg Pro Gln Ile Asn Gly Lys Tyr Ile 24352440 2445 Leu His Asp Asn Gly Thr Leu Val Ile Lys Glu Ala Thr Ala Tyr2450 2455 2460 Asp Arg Gly Asn Tyr Ile Cys Lys Ala Gln Asn Ser Val GlyHis 2465 2470 2475 Thr Leu Ile Thr Val Pro Val Met Ile Val Ala Tyr ProPro Arg 2480 2485 2490 Ile Thr Asn Arg Pro Pro Arg Ser Ile Val Thr ArgThr Gly Ala 2495 2500 2505 Ala Phe Gln Leu His Cys Val Ala Leu Gly ValPro Lys Pro Glu 2510 2515 2520 Ile Thr Trp Glu Met Pro Asp His Ser LeuLeu Ser Thr Ala Ser 2525 2530 2535 Lys Glu Arg Thr His Gly Ser Glu GlnLeu His Leu Gln Gly Thr 2540 2545 2550 Leu Val Ile Gln Asn Pro Gln ThrSer Asp Ser Gly Ile Tyr Lys 2555 2560 2565 Cys Thr Ala Lys Asn Pro LeuGly Ser Asp Tyr Ala Ala Thr Tyr 2570 2575 2580 Ile Gln Val 2585 12 236PRT Mus musculus misc_feature (1)..(236) ′x′ can be any amino acid 12Met Gln Lys Arg Gly Arg Glu Val Ser Cys Leu Leu Ile Ser Leu Thr 1 5 1015 Ala Ile Cys Leu Val Val Thr Pro Gly Ser Arg Val Cys Pro Arg Arg 20 2530 Cys Ala Cys Tyr Val Pro Thr Glu Val His Cys Thr Phe Arg Asp Leu 35 4045 Thr Ser Ile Pro Asp Gly Pro Ala Asn Val Glu Arg Val Asn Leu Gly 50 5560 Tyr Asn Ser Leu Thr Arg Leu Thr Glu Asn Asp Phe Ser Gly Leu Ser 65 7075 80 Arg Leu Glu Leu Leu Met Leu His Ser Asn Gly Ile His Arg Val Ser 8590 95 Asp Lys Thr Phe Ser Gly Leu Gln Ser Leu Gln Val Leu Lys Met Ser100 105 110 Tyr Asn Lys Val Gln Ile Ile Glu Lys Asp Thr Leu Tyr Gly LeuArg 115 120 125 Ser Leu Thr Arg Leu His Leu Asp His Asn Asn Ile Glu PheIle Asn 130 135 140 Pro Glu Ala Phe Tyr Gly Leu Thr Leu Leu Arg Leu ValHis Leu Glu 145 150 155 160 Gly Asn Arg Leu Thr Lys Leu His Pro Asp ThrPhe Val Ser Leu Ser 165 170 175 Tyr Leu Gln Ile Phe Lys Thr Ser Phe IleLys Xaa Leu Tyr Leu Tyr 180 185 190 Asp Asn Phe Thr Ser Leu Pro Lys GluMet Val Ser Ser Met Pro Asn 195 200 205 Leu Glu Ser Leu Tyr Leu His GlyAsn Pro Trp Thr Cys Asp Cys His 210 215 220 Leu Lys Trp Leu Ser Glu TrpMet Gln Gly Asn Pro 225 230 235 13 2597 PRT Rattus sp. misc_feature(1)..(2597) ′x′ can be any amino acid 13 Met Gln Val Arg Gly Arg Glu ValSer Gly Leu Leu Ile Ser Leu Thr 1 5 10 15 Ala Val Cys Leu Val Val ThrPro Gly Ser Arg Ala Cys Pro Arg Arg 20 25 30 Cys Ala Cys Tyr Val Pro ThrGlu Val His Cys Thr Phe Arg Tyr Leu 35 40 45 Thr Ser Ile Pro Asp Gly IlePro Ala Asn Val Glu Arg Ile Asn Leu 50 55 60 Gly Tyr Asn Ser Leu Thr ArgLeu Thr Glu Asn Asp Phe Asp Gly Leu 65 70 75 80 Ser Lys Leu Glu Leu LeuMet Leu His Ser Asn Gly Ile His Arg Val 85 90 95 Ser Asp Lys Thr Phe SerGly Leu Gln Ser Leu Gln Val Leu Lys Met 100 105 110 Ser Tyr Asn Lys ValGln Ile Ile Arg Lys Asp Thr Phe Tyr Gly Leu 115 120 125 Gly Ser Leu ValArg Leu His Leu Asp His Asn Asn Ile Glu Phe Ile 130 135 140 Asn Pro GluAla Phe Tyr Gly Leu Thr Ser Leu Arg Leu Val His Leu 145 150 155 160 GluGly Asn Arg Leu Thr Lys Leu His Pro Asp Thr Phe Val Ser Leu 165 170 175Ser Tyr Leu Gln Ile Phe Lys Thr Ser Phe Ile Lys Tyr Leu Phe Leu 180 185190 Ser Asp Asn Phe Leu Thr Ser Leu Pro Lys Glu Met Val Ser Tyr Met 195200 205 Pro Asn Leu Glu Ser Leu Tyr Leu His Gly Asn Pro Trp Thr Cys Asp210 215 220 Cys His Leu Lys Trp Leu Ser Glu Trp Met Gln Gly Asn Pro AspIle 225 230 235 240 Ile Lys Cys Lys Lys Asp Arg Ser Ser Ser Ser Pro GlnGln Cys Pro 245 250 255 Leu Cys Met Asn Pro Arg Ile Ser Lys Gly Arg ProPhe Ala Met Val 260 265 270 Pro Ser Gly Ala Phe Leu Cys Thr Lys Pro ThrIle Asp Pro Ser Leu 275 280 285 Lys Ser Lys Ser Leu Val Thr Gln Glu AspAsn Gly Ser Ala Ser Thr 290 295 300 Ser Pro Gln Asp Phe Ile Glu Pro PheGly Ser Leu Ser Leu Asn Met 305 310 315 320 Thr Xaa Xaa Ser Gly Asn LysAla Asp Met Val Cys Ser Ile Gln Lys 325 330 335 Pro Ser Arg Thr Ser ProThr Ala Phe Thr Glu Glu Asn Asp Tyr Ile 340 345 350 Met Leu Asn Ala SerPhe Ser Thr Asn Leu Val Cys Ser Val Asp Tyr 355 360 365 Asn His Ile GlnPro Val Trp Gln Leu Leu Ala Leu Tyr Ser Asp Ser 370 375 380 Pro Leu IleLeu Glu Arg Lys Pro Gln Leu Thr Glu Thr Pro Ser Leu 385 390 395 400 SerSer Arg Tyr Lys Gln Val Ala Leu Arg Pro Glu Asp Ile Phe Thr 405 410 415Ser Ile Glu Ala Asp Val Arg Ala Asp Pro Phe Trp Phe Gln Gln Glu 420 425430 Lys Ile Val Leu Gln Leu Asn Arg Thr Ala Thr Thr Leu Ser Thr Leu 435440 445 Gln Ile Gln Phe Ser Thr Asp Ala Gln Ile Ala Leu Pro Arg Ala Glu450 455 460 Met Arg Ala Glu Arg Leu Lys Trp Thr Met Ile Leu Met Met AsnAsn 465 470 475 480 Pro Lys Leu Glu Arg Thr Val Leu Val Gly Gly Thr IleAla Leu Ser 485 490 495 Cys Pro Gly Lys Gly Asp Pro Ser Pro His Leu GluTrp Leu Leu Ala 500 505 510 Asp Gly Ser Lys Val Arg Ala Pro Tyr Val SerGlu Asp Gly Arg Ile 515 520 525 Leu Ile Asp Lys Asn Gly Lys Leu Glu LeuGln Met Ala Asp Ser Phe 530 535 540 Asp Ala Gly Leu Tyr His Cys Ile SerThr Asn Asp Ala Asp Ala Asp 545 550 555 560 Val Leu Thr Tyr Arg Ile ThrVal Val Glu Pro Tyr Gly Glu Ser Thr 565 570 575 His Asp Ser Gly Val GlnHis Thr Val Val Thr Gly Glu Thr Leu Asp 580 585 590 Leu Pro Cys Leu SerThr Gly Val Pro Asp Ala Ser Ile Ser Trp Ile 595 600 605 Leu Pro Gly AsnThr Val Phe Ser Gln Pro Ser Arg Asp Arg Gln Ile 610 615 620 Leu Asn AsnGly Thr Leu Arg Ile Leu Gln Val Thr Pro Lys Asp Gln 625 630 635 640 GlyHis Tyr Gln Cys Val Ala Ala Asn Pro Ser Gly Ala Asp Phe Ser 645 650 655Ser Phe Lys Val Ser Val Gln Lys Lys Gly Gln Arg Met Val Glu His 660 665670 Asp Arg Glu Ala Gly Gly Ser Gly Leu Gly Glu Pro Asn Ser Ser Val 675680 685 Ser Leu Lys Gln Pro Ala Ser Leu Lys Leu Ser Ala Ser Ala Leu Thr690 695 700 Gly Ser Glu Ala Gly Lys Gln Val Ser Gly Val His Arg Lys AsnLys 705 710 715 720 His Arg Asp Leu Ile His Arg Arg Arg Gly Asp Ser ThrLeu Arg Arg 725 730 735 Phe Arg Glu His Arg Arg Gln Leu Pro Leu Ser AlaArg Arg Ile Asp 740 745 750 Pro Gln Arg Trp Ala Ala Leu Leu Glu Lys AlaLys Lys Asn Ser Val 755 760 765 Pro Lys Lys Gln Glu Asn Thr Thr Val LysPro Val Pro Leu Ala Val 770 775 780 Pro Leu Val Glu Leu Thr Asp Glu GluLys Asp Ala Ser Gly Met Ile 785 790 795 800 Pro Pro Asp Glu Glu Phe MetVal Leu Lys Thr Lys Ala Ser Gly Val 805 810 815 Pro Gly Arg Ser Pro ThrAla Asp Ser Gly Pro Val Asn His Gly Phe 820 825 830 Met Thr Ser Ile AlaSer Gly Thr Glu Val Ser Thr Val Asn Pro Gln 835 840 845 Thr Leu Gln SerGlu His Leu Pro Asp Phe Lys Leu Phe Ser Val Thr 850 855 860 Asn Gly ThrAla Val Thr Lys Ser Met Asn Pro Ser Ile Ala Ser Lys 865 870 875 880 IleGlu Asp Thr Thr Asn Gln Asn Pro Ile Ile Ile Phe Pro Ser Val 885 890 895Ala Glu Ile Arg Asp Ser Ala Gln Ala Gly Arg Ala Ser Ser Gln Ser 900 905910 Ala His Pro Val Thr Gly Gly Asn Met Ala Thr Tyr Gly His Thr Asn 915920 925 Thr Tyr Ser Ser Phe Thr Ser Lys Ala Ser Thr Val Leu Gln Pro Ile930 935 940 Asn Pro Thr Glu Ser Tyr Gly Pro Gln Ile Pro Ile Thr Gly ValSer 945 950 955 960 Arg Pro Ser Ser Ser Asp Ile Ser Ser His Thr Thr AlaAsp Pro Ser 965 970 975 Phe Ser Ser His Pro Ser Gly Ser His Thr Thr AlaSer Ser Leu Phe 980 985 990 His Ile Pro Arg Asn Asn Asn Thr Gly Asn PhePro Leu Ser Arg His 995 1000 1005 Leu Gly Arg Glu Arg Thr Ile Trp SerArg Gly Arg Val Lys Asn 1010 1015 1020 Pro His Arg Thr Pro Val Leu ArgArg His Arg His Arg Thr Val 1025 1030 1035 Arg Pro Ala Ile Lys Gly ProAla Asn Lys Asn Val Ser Gln Val 1040 1045 1050 Pro Ala Thr Glu Tyr ProGly Met Cys His Thr Cys Pro Ser Ala 1055 1060 1065 Glu Gly Leu Thr ValAla Thr Ala Ala Leu Ser Val Pro Ser Ser 1070 1075 1080 Ser His Ser AlaLeu Pro Lys Thr Asn Asn Val Gly Val Ile Ala 1085 1090 1095 Glu Glu SerThr Thr Val Val Lys Lys Pro Leu Leu Leu Phe Lys 1100 1105 1110 Asp LysGln Asn Val Asp Ile Glu Ile Ile Thr Thr Thr Thr Lys 1115 1120 1125 TyrSer Gly Gly Glu Ser Asn His Val Ile Pro Thr Glu Ala Ser 1130 1135 1140Met Thr Ser Ala Pro Thr Ser Val Ser Leu Gly Lys Ser Pro Val 1145 11501155 Asp Asn Ser Gly His Leu Ser Met Pro Gly Thr Ile Gln Thr Gly 11601165 1170 Lys Asp Ser Val Glu Thr Thr Pro Leu Pro Ser Pro Leu Ser Thr1175 1180 1185 Pro Ser Ile Pro Thr Ser Thr Lys Phe Ser Lys Arg Lys ThrPro 1190 1195 1200 Leu His Gln Ile Phe Val Asn Asn Gln Lys Lys Glu GlyMet Leu 1205 1210 1215 Lys Asn Pro Tyr Gln Phe Gly Leu Gln Lys Asn ProAla Ala Lys 1220 1225 1230 Leu Pro Lys Ile Ala Pro Leu Leu Pro Thr GlyGln Ser Ser Pro 1235 1240 1245 Ser Asp Ser Thr Thr Leu Leu Thr Ser ProPro Pro Ala Leu Ser 1250 1255 1260 Thr Thr Met Ala Ala Thr Gln Asn LysGly Thr Glu Val Val Ser 1265 1270 1275 Gly Ala Arg Ser Leu Ser Ala GlyLys Lys Gln Pro Phe Thr Asn 1280 1285 1290 Ser Ser Pro Val Leu Pro SerThr Ile Ser Lys Arg Ser Asn Thr 1295 1300 1305 Leu Asn Phe Leu Ser ThrGlu Thr Pro Thr Val Thr Ser Pro Thr 1310 1315 1320 Ala Thr Ala Ser ValIle Met Ser Glu Thr Gln Arg Thr Arg Ser 1325 1330 1335 Lys Glu Ala LysAsp Gln Ile Lys Gly Pro Arg Lys Asn Arg Asn 1340 1345 1350 Asn Ala AsnThr Thr Pro Arg Gln Val Ser Gly Tyr Ser Ala Tyr 1355 1360 1365 Ser AlaLeu Thr Thr Ala Asp Thr Pro Leu Ala Phe Ser His Ser 1370 1375 1380 ProArg Gln Asp Asp Gly Gly Asn Val Ser Ala Val Ala Tyr His 1385 1390 1395Ser Thr Thr Ser Leu Leu Ala Ile Thr Glu Leu Phe Glu Lys Tyr 1400 14051410 Thr Gln Thr Leu Gly Asn Thr Thr Ala Leu Glu Thr Thr Leu Leu 14151420 1425 Ser Lys Ser Gln Glu Ser Thr Thr Val Lys Arg Ala Ser Asp Thr1430 1435 1440 Pro Pro Pro Leu Leu Ser Ser Gly Ala Pro Pro Val Pro ThrPro 1445 1450 1455 Ser Pro Pro Pro Phe Thr Lys Gly Val Val Thr Asp SerLys Val 1460 1465 1470 Thr Ser Ala Phe Gln Met Thr Ser Asn Arg Val ValThr Ile Tyr 1475 1480 1485 Glu Ser Ser Arg His Asn Thr Asp Leu Gln GlnPro Ser Ala Glu 1490 1495 1500 Ala Ser Pro Asn Pro Glu Ile Ile Thr GlyThr Thr Asp Ser Pro 1505 1510 1515 Ser Asn Leu Phe Pro Ser Thr Ser ValPro Ala Leu Arg Val Asp 1520 1525 1530 Lys Pro Gln Asn Ser Lys Trp LysPro Ser Pro Trp Pro Glu His 1535 1540 1545 Lys Tyr Gln Leu Lys Ser TyrSer Glu Thr Ile Glu Lys Gly Lys 1550 1555 1560 Arg Pro Ala Val Ser MetSer Pro His Leu Ser Leu Pro Glu Ala 1565 1570 1575 Ser Thr His Ala SerHis Trp Asn Thr Gln Lys His Ala Glu Lys 1580 1585 1590 Ser Val Phe AspLys Lys Pro Gly Gln Asn Pro Thr Ser Lys His 1595 1600 1605 Leu Pro TyrVal Ser Leu Pro Lys Thr Leu Leu Lys Lys Pro Arg 1610 1615 1620 Ile IleGly Gly Lys Ala Ala Ser Phe Thr Val Pro Ala Asn Ser 1625 1630 1635 AspVal Phe Leu Pro Cys Glu Ala Val Gly Asp Pro Leu Pro Ile 1640 1645 1650Ile His Trp Thr Arg Val Ser Ser Gly Xaa Glu Ile Ser Gln Gly 1655 16601665 Thr Gln Lys Ser Arg Phe His Val Leu Pro Asn Gly Thr Leu Ser 16701675 1680 Ile Gln Arg Val Ser Ile Gln Asp Arg Gly Gln Tyr Leu Cys Ser1685 1690 1695 Ala Phe Asn Pro Leu Gly Val Asp His Phe His Val Ser LeuSer 1700 1705 1710 Val Val Phe Tyr Pro Ala Arg Ile Leu Asp Arg His ValLys Glu 1715 1720 1725 Ile Thr Val His Phe Gly Ser Thr Val Glu Leu LysCys Arg Val 1730 1735 1740 Glu Gly Met Pro Arg Pro Thr Val Ser Trp IleLeu Ala Asn Gln 1745 1750 1755 Thr Val Val Ser Glu Thr Ala Lys Gly SerArg Lys Val Trp Val 1760 1765 1770 Thr Pro Asp Gly Thr Leu Ile Ile TyrAsn Leu Ser Leu Tyr Asp 1775 1780 1785 Arg Gly Phe Tyr Lys Cys Val AlaSer Asn Pro Ser Gly Gln Asp 1790 1795 1800 Ser Leu Leu Val Lys Ile GlnVal Ile Thr Ala Pro Pro Val Ile 1805 1810 1815 Ile Glu Gln Lys Arg GlnAla Ile Val Gly Val Leu Gly Gly Ser 1820 1825 1830 Leu Lys Leu Pro CysThr Ala Lys Gly Thr Pro Gln Pro Ser Val 1835 1840 1845 His Trp Val LeuTyr Asp Gly Thr Glu Leu Lys Pro Leu Gln Leu 1850 1855 1860 Thr His SerArg Phe Phe Leu Tyr Pro Asn Gly Thr Leu Tyr Ile 1865 1870 1875 Arg SerIle Ala Pro Ser Val Arg Gly Thr Tyr Glu Cys Ile Ala 1880 1885 1890 ThrSer Ser Ser Gly Ser Glu Arg Arg Val Val Ile Leu Thr Val 1895 1900 1905Glu Glu Gly Glu Thr Ile Pro Arg Ile Glu Thr Ala Ser Gln Lys 1910 19151920 Trp Thr Glu Val Asn Leu Gly Glu Lys Leu Leu Leu Asn Cys Ser 19251930 1935 Ala Thr Gly Asp Pro Lys Pro Arg Ile Ile Trp Arg Leu Pro Ser1940 1945 1950 Lys Ala Val Ile Asp Gln Trp His Arg Met Gly Ser Arg IleHis 1955 1960 1965 Val Tyr Pro Asn Gly Ser Leu Val Val Gly Ser Val ThrGlu Lys 1970 1975 1980 Asp Ala Gly Asp Tyr Leu Cys Val Ala Arg Asn LysMet Gly Asp 1985 1990 1995 Asp Leu Val Leu Met His Val Arg Leu Arg LeuThr Pro Ala Lys 2000 2005 2010 Ile Glu Gln Lys Gln Tyr Phe Lys Lys GlnVal Leu His Gly Lys 2015 2020 2025 Asp Phe Gln Val Asp Cys Lys Ala SerGly Ser Pro Val Pro Glu 2030 2035 2040 Val Ser Trp Ser Leu Pro Asp GlyThr Val Leu Asn Asn Val Ala 2045 2050 2055 Gln Ala Asp Asp Ser Gly TyrArg Thr Lys Arg Tyr Thr Leu Phe 2060 2065 2070 His Asn Gly Thr Leu TyrPhe Asn Asn Val Gly Met Ala Glu Glu 2075 2080 2085 Gly Asp Tyr Ile CysSer Ala Gln Asn Thr Leu Gly Lys Asp Glu 2090 2095 2100 Met Lys Val HisLeu Thr Val Leu Thr Ala Ile Pro Arg Ile Arg 2105 2110 2115 Gln Ser TyrLys Thr Thr Met Arg Leu Arg Ala Gly Glu Thr Ala 2120 2125 2130 Val LeuAsp Cys Glu Val Thr Gly Glu Pro Lys Pro Asn Val Phe 2135 2140 2145 TrpLeu Leu Pro Ser Asn Asn Val Ile Ser Phe Ser Asn Asp Arg 2150 2155 2160Phe Thr Phe His Ala Asn Arg Thr Leu Ser Ile His Lys Val Lys 2165 21702175 Pro Leu Asp Ser Gly Asp Tyr Val Cys Val Ala Gln Asn Pro Ser 21802185 2190 Gly Asp Asp Thr Lys Thr Tyr Lys Leu Asp Ile Val Ser Lys Pro2195 2200 2205 Pro Leu Ile Asn Gly Leu Tyr Ala Asn Lys Thr Val Ile LysAla 2210 2215 2220 Thr Ala Ile Arg His Ser Lys Lys Tyr Phe Asp Cys ArgAla Asp 2225 2230 2235 Gly Ile Pro Ser Ser Gln Val Thr Trp Ile Met ProGly Asn Ile 2240 2245 2250 Phe Leu Pro Ala Pro Tyr Phe Gly Ser Arg ValThr Val His Pro 2255 2260 2265 Asn Gly Thr Leu Glu Met Arg Asn Ile ArgLeu Ser Asp Ser Ala 2270 2275 2280 Asp Phe Thr Cys Val Val Arg Ser GluGly Gly Glu Ser Val Leu 2285 2290 2295 Val Val Gln Leu Glu Val Leu GluMet Leu Arg Arg Pro Thr Phe 2300 2305 2310 Arg Asn Pro Phe Asn Glu LysVal Ile Ala Gln Ala Gly Lys Pro 2315 2320 2325 Val Ala Leu Asn Cys SerVal Asp Gly Asn Pro Pro Pro Glu Ile 2330 2335 2340 Thr Trp Ile Leu ProAsp Gly Thr Gln Phe Ala Asn Arg Pro His 2345 2350 2355 Asn Ser Pro TyrLeu Met Ala Gly Asn Gly Ser Leu Ile Leu Tyr 2360 2365 2370 Lys Ala ThrArg Asn Lys Ser Gly Lys Tyr Arg Cys Ala Ala Arg 2375 2380 2385 Asn LysVal Gly Tyr Ile Glu Lys Leu Ile Leu Leu Glu Ile Gly 2390 2395 2400 GlnLys Pro Val Ile Leu Thr Tyr Glu Pro Gly Met Val Lys Ser 2405 2410 2415Val Ser Gly Glu Pro Leu Ser Leu His Cys Val Ser Asp Gly Ile 2420 24252430 Pro Lys Pro Asn Val Lys Trp Thr Thr Pro Gly Gly His Val Ile 24352440 2445 Asp Arg Pro Gln Val Asp Gly Lys Tyr Ile Leu His Glu Asn Gly2450 2455 2460 Thr Leu Val Ile Lys Ala Thr Thr Ala His Asp Gln Gly AsnTyr 2465 2470 2475 Ile Cys Arg Ala Gln Asn Ser Val Gly Gln Ala Val IleSer Val 2480 2485 2490 Ser Val Met Val Val Ala Tyr Pro Pro Arg Ile IleAsn Tyr Leu 2495 2500 2505 Pro Arg Asn Met Leu Arg Arg Thr Gly Glu AlaMet Gln Leu His 2510 2515 2520 Cys Val Ala Leu Gly Ile Pro Lys Pro LysVal Thr Trp Glu Thr 2525 2530 2535 Pro Arg His Ser Leu Leu Ser Lys AlaThr Ala Arg Lys Pro His 2540 2545 2550 Arg Ser Glu Met Leu His Pro GlnGly Thr Leu Val Ile Gln Asn 2555 2560 2565 Leu Gln Thr Ser Asp Ser GlyVal Tyr Lys Cys Arg Ala Gln Asn 2570 2575 2580 Leu Leu Gly Thr Asp TyrAla Thr Thr Tyr Ile Gln Val Leu 2585 2590 2595 14 2586 PRT Homo sapiens14 15 236 PRT Mus musculus misc_feature (1)..(236) ′x′ can be any aminoacid 15 Met Gln Lys Arg Gly Arg Glu Val Ser Cys Leu Leu Ile Ser Leu Thr1 5 10 15 Ala Ile Cys Leu Val Val Thr Pro Gly Ser Arg Val Cys Pro ArgArg 20 25 30 Cys Ala Cys Tyr Val Pro Thr Glu Val His Cys Thr Phe Arg AspLeu 35 40 45 Thr Ser Ile Pro Asp Gly Pro Ala Asn Val Glu Arg Val Asn LeuGly 50 55 60 Tyr Asn Ser Leu Thr Arg Leu Thr Glu Asn Asp Phe Ser Gly LeuSer 65 70 75 80 Arg Leu Glu Leu Leu Met Leu His Ser Asn Gly Ile His ArgVal Ser 85 90 95 Asp Lys Thr Phe Ser Gly Leu Gln Ser Leu Gln Val Leu LysMet Ser 100 105 110 Tyr Asn Lys Val Gln Ile Ile Glu Lys Asp Thr Leu TyrGly Leu Arg 115 120 125 Ser Leu Thr Arg Leu His Leu Asp His Asn Asn IleGlu Phe Ile Asn 130 135 140 Pro Glu Ala Phe Tyr Gly Leu Thr Leu Leu ArgLeu Val His Leu Glu 145 150 155 160 Gly Asn Arg Leu Thr Lys Leu His ProAsp Thr Phe Val Ser Leu Ser 165 170 175 Tyr Leu Gln Ile Phe Lys Thr SerPhe Ile Lys Xaa Leu Tyr Leu Tyr 180 185 190 Asp Asn Phe Thr Ser Leu ProLys Glu Met Val Ser Ser Met Pro Asn 195 200 205 Leu Glu Ser Leu Tyr LeuHis Gly Asn Pro Trp Thr Cys Asp Cys His 210 215 220 Leu Lys Trp Leu SerGlu Trp Met Gln Gly Asn Pro 225 230 235 16 2587 PRT homo sapiens 16 MetLys Val Lys Gly Arg Gly Ile Thr Cys Leu Leu Val Ser Phe Ala 1 5 10 15Val Ile Cys Leu Val Ala Thr Pro Gly Gly Lys Ala Cys Pro Arg Arg 20 25 30Cys Ala Cys Tyr Met Pro Thr Glu Val His Cys Thr Phe Arg Tyr Leu 35 40 45Thr Ser Ile Pro Asp Ser Ile Pro Pro Asn Val Glu Arg Ile Asn Leu 50 55 60Gly Tyr Asn Ser Leu Val Arg Leu Met Glu Thr Asp Phe Ser Gly Leu 65 70 7580 Thr Lys Leu Glu Leu Leu Met Leu His Ser Asn Gly Ile His Thr Ile 85 9095 Pro Asp Lys Thr Phe Ser Asp Leu Gln Ala Leu Gln Val Leu Lys Met 100105 110 Ser Tyr Asn Lys Val Arg Lys Leu Gln Lys Asp Thr Phe Tyr Gly Leu115 120 125 Arg Ser Leu Thr Arg Leu His Met Asp His Asn Asn Ile Glu PheIle 130 135 140 Asn Pro Glu Val Phe Tyr Gly Leu Asn Phe Leu Arg Leu ValHis Leu 145 150 155 160 Glu Gly Asn Gln Leu Thr Lys Leu His Pro Asp ThrPhe Val Ser Leu 165 170 175 Ser Tyr Leu Gln Ile Phe Lys Ile Ser Phe IleLys Phe Leu Tyr Leu 180 185 190 Ser Asp Asn Phe Leu Thr Ser Leu Pro GlnGlu Met Val Ser Tyr Met 195 200 205 Pro Asp Leu Asp Ser Leu Tyr Leu HisGly Asn Pro Trp Thr Cys Asp 210 215 220 Cys His Leu Lys Trp Leu Ser AspTrp Ile Gln Pro Asp Val Ile Lys 225 230 235 240 Cys Lys Lys Asp Arg SerPro Ser Ser Ala Gln Gln Cys Pro Leu Cys 245 250 255 Met Asn Pro Arg ThrSer Lys Gly Lys Pro Leu Ala Met Val Ser Ala 260 265 270 Ala Ala Phe GlnCys Ala Lys Pro Thr Ile Asp Ser Ser Leu Lys Ser 275 280 285 Lys Ser LeuThr Ile Leu Glu Asp Ser Ser Ser Ala Phe Ile Ser Pro 290 295 300 Gln GlyPhe Met Ala Pro Phe Gly Ser Leu Thr Leu Asn Met Thr Asp 305 310 315 320Gln Ser Gly Asn Glu Ala Asn Met Val Cys Ser Ile Gln Lys Pro Ser 325 330335 Arg Thr Ser Pro Ile Ala Phe Thr Glu Glu Asn Asp Tyr Ile Val Leu 340345 350 Asn Thr Ser Phe Ser Thr Phe Leu Val Cys Asn Ile Asp Tyr Gly His355 360 365 Ile Gln Pro Val Trp Gln Ile Leu Ala Leu Tyr Ser Asp Ser ProLeu 370 375 380 Ile Leu Glu Arg Ser His Leu Leu Ser Glu Thr Pro Gln LeuTyr Tyr 385 390 395 400 Lys Tyr Lys Gln Val Ala Pro Lys Pro Glu Asp IlePhe Thr Asn Ile 405 410 415 Glu Ala Asp Leu Arg Ala Asp Pro Ser Trp LeuMet Gln Asp Gln Ile 420 425 430 Ser Leu Gln Leu Asn Arg Thr Ala Thr ThrPhe Ser Thr Leu Gln Ile 435 440 445 Gln Tyr Ser Ser Asp Ala Gln Ile ThrLeu Pro Arg Ala Glu Met Arg 450 455 460 Pro Val Lys His Lys Trp Thr MetIle Ser Arg Asp Asn Asn Thr Lys 465 470 475 480 Leu Glu His Thr Val LeuVal Gly Gly Thr Val Gly Leu Asn Cys Pro 485 490 495 Gly Gln Gly Asp ProThr Pro His Val Asp Trp Leu Leu Ala Asp Gly 500 505 510 Ser Lys Val ArgAla Pro Tyr Val Ser Glu Asp Gly Arg Ile Leu Ile 515 520 525 Asp Lys SerGly Lys Leu Glu Leu Gln Met Ala Asp Ser Phe Asp Thr 530 535 540 Gly ValTyr His Cys Ile Ser Ser Asn Tyr Asp Asp Ala Asp Ile Leu 545 550 555 560Thr Tyr Arg Ile Thr Val Val Glu Pro Leu Val Glu Ala Tyr Gln Glu 565 570575 Asn Gly Ile His His Thr Val Phe Ile Gly Glu Thr Leu Asp Leu Pro 580585 590 Cys His Ser Thr Gly Ile Pro Asp Ala Ser Ile Ser Trp Val Ile Pro595 600 605 Gly Asn Asn Val Leu Tyr Gln Ser Ser Arg Asp Lys Lys Val LeuAsn 610 615 620 Asn Gly Thr Leu Arg Ile Leu Gln Val Thr Pro Lys Asp GlnGly Tyr 625 630 635 640 Tyr Arg Cys Val Ala Ala Asn Pro Ser Gly Val AspPhe Leu Ile Phe 645 650 655 Gln Val Ser Val Lys Met Lys Gly Gln Arg ProLeu Glu His Asp Gly 660 665 670 Glu Thr Glu Gly Ser Gly Leu Asp Glu SerAsn Pro Ile Ala His Leu 675 680 685 Lys Glu Pro Pro Gly Ala Gln Leu ArgThr Ser Ala Leu Met Glu Ala 690 695 700 Glu Val Gly Lys His Thr Ser SerThr Ser Lys Arg His Asn Tyr Arg 705 710 715 720 Glu Leu Thr Leu Gln ArgArg Gly Asp Ser Thr His Arg Arg Phe Arg 725 730 735 Glu Asn Arg Arg HisPhe Pro Pro Ser Ala Arg Arg Ile Asp Pro Gln 740 745 750 His Trp Ala AlaLeu Leu Glu Lys Ala Lys Lys Asn Ala Met Pro Asp 755 760 765 Lys Arg GluAsn Thr Thr Val Ser Pro Pro Pro Val Val Thr Gln Leu 770 775 780 Pro AsnIle Pro Gly Glu Glu Asp Asp Ser Ser Gly Met Leu Ala Leu 785 790 795 800His Glu Glu Phe Met Val Pro Ala Thr Lys Ala Leu Asn Leu Pro Ala 805 810815 Arg Thr Val Thr Ala Asp Ser Arg Thr Ile Ser Asp Ser Pro Met Thr 820825 830 Asn Ile Asn Tyr Gly Thr Glu Phe Ser Pro Val Val Asn Ser Gln Ile835 840 845 Leu Pro Pro Glu Glu Pro Thr Asp Phe Lys Leu Ser Thr Ala IleLys 850 855 860 Thr Thr Ala Met Ser Lys Asn Ile Asn Pro Thr Met Ser SerGln Ile 865 870 875 880 Gln Gly Thr Thr Asn Gln His Ser Ser Thr Val PhePro Leu Leu Leu 885 890 895 Gly Ala Thr Glu Phe Gln Asp Ser Asp Gln MetGly Arg Gly Arg Glu 900 905 910 His Phe Gln Ser Arg Pro Pro Ile Thr ValArg Thr Met Ile Lys Asp 915 920 925 Val Asn Val Lys Met Leu Ser Ser ThrThr Asn Lys Leu Leu Leu Glu 930 935 940 Ser Val Asn Thr Thr Asn Ser HisGln Thr Ser Val Arg Glu Val Ser 945 950 955 960 Glu Pro Arg His Asn HisPhe Tyr Ser His Thr Thr Gln Ile Leu Ser 965 970 975 Thr Ser Thr Phe ProSer Asp Pro His Thr Ala Ala His Ser Gln Phe 980 985 990 Pro Ile Pro ArgAsn Ser Thr Val Asn Ile Pro Leu Phe Arg Arg Phe 995 1000 1005 Gly ArgGln Arg Lys Ile Gly Gly Arg Gly Arg Ile Ile Ser Pro 1010 1015 1020 TyrArg Thr Pro Val Leu Arg Arg His Arg Tyr Ser Ile Phe Arg 1025 1030 1035Ser Thr Thr Arg Gly Ser Ser Glu Lys Ser Thr Thr Ala Phe Ser 1040 10451050 Ala Thr Val Leu Asn Val Thr Cys Leu Ser Cys Leu Pro Arg Glu 10551060 1065 Arg Leu Thr Thr Ala Thr Ala Ala Leu Ser Phe Pro Ser Ala Ala1070 1075 1080 Pro Ile Thr Phe Pro Lys Ala Asp Ile Ala Arg Val Pro SerGlu 1085 1090 1095 Glu Ser Thr Thr Leu Val Gln Asn Pro Leu Leu Leu LeuGlu Asn 1100 1105 1110 Lys Pro Ser Val Glu Lys Thr Thr Pro Thr Ile LysTyr Phe Arg 1115 1120 1125 Thr Glu Ile Ser Gln Val Thr Pro Thr Gly AlaVal Met Thr Tyr 1130 1135 1140 Ala Pro Thr Ser Ile Pro Met Glu Lys ThrHis Lys Val Asn Ala 1145 1150 1155 Ser Tyr Pro Arg Val Ser Ser Thr AsnGlu Ala Lys Arg Asp Ser 1160 1165 1170 Val Ile Thr Ser Ser Leu Ser GlyAla Ile Thr Lys Pro Pro Met 1175 1180 1185 Thr Ile Ile Ala Ile Thr ArgPhe Ser Arg Arg Lys Ile Pro Trp 1190 1195 1200 Gln Gln Asn Phe Val AsnAsn His Asn Pro Lys Gly Arg Leu Arg 1205 1210 1215 Asn Gln His Lys ValSer Leu Gln Lys Ser Thr Ala Val Met Leu 1220 1225 1230 Pro Lys Thr SerPro Ala Leu Pro Gln Arg Gln Ser Ser Pro Phe 1235 1240 1245 His Phe ThrThr Leu Ser Thr Ser Val Met Gln Ile Pro Ser Asn 1250 1255 1260 Thr LeuThr Thr Ala His His Thr Thr Thr Lys Thr His Asn Pro 1265 1270 1275 GlySer Leu Pro Thr Lys Lys Glu Leu Pro Phe Pro Pro Leu Asn 1280 1285 1290Pro Met Leu Pro Ser Ile Ile Ser Lys Asp Ser Ser Thr Lys Ser 1295 13001305 Ile Ile Ser Thr Gln Thr Ala Ile Pro Ala Thr Thr Pro Thr Phe 13101315 1320 Pro Ala Ser Val Ile Thr Tyr Glu Thr Gln Thr Glu Arg Ser Arg1325 1330 1335 Ala Gln Thr Ile Gln Arg Glu Gln Glu Pro Gln Lys Lys AsnArg 1340 1345 1350 Thr Asp Pro Asn Ile Ser Pro Asp Gln Ser Ser Gly PheThr Thr 1355 1360 1365 Pro Thr Ala Met Thr Pro Pro Ala Leu Ala Phe ThrHis Ser Pro 1370 1375 1380 Pro Glu Asn Thr Thr Gly Ile Ser Ser Thr IleSer Phe His Ser 1385 1390 1395 Arg Thr Leu Asn Leu Thr Asp Val Ile GluGlu Leu Ala Gln Ala 1400 1405 1410 Ser Thr Gln Thr Leu Lys Ser Thr IleAla Ser Glu Thr Thr Leu 1415 1420 1425 Ser Ser Lys Ser His Gln Ser ThrThr Thr Arg Lys Ala Ser Leu 1430 1435 1440 Asp Thr Pro Ile Pro Pro PheLeu Ser Ser Ser Ala Thr Leu Met 1445 1450 1455 Pro Val Pro Ile Ser ProPro Phe Thr Gln Arg Ala Val Thr Asp 1460 1465 1470 Thr Arg Gly Asp SerHis Phe Arg Leu Met Thr Asn Thr Val Val 1475 1480 1485 Lys Leu His GluSer Ser Arg His Asn Leu Gln Met Pro Ser Ser 1490 1495 1500 Gln Leu GluPro Leu Thr Ser Ser Thr Ser Asn Leu Leu His Ser 1505 1510 1515 Thr ProMet Pro Ala Leu Thr Thr Val Lys Ser Gln Asn Ser Lys 1520 1525 1530 LeuThr Pro Ser Pro Trp Ala Glu Tyr Gln Phe Trp His Lys Pro 1535 1540 1545Tyr Ser Asp Ile Ala Glu Lys Gly Lys Lys Pro Glu Val Ser Met 1550 15551560 Leu Ala Thr Thr Gly Leu Ser Glu Ala Thr Thr Leu Val Ser Asp 15651570 1575 Trp Asp Gly Gln Lys Asn Thr Lys Lys Ser Asp Phe Asp Lys Lys1580 1585 1590 Pro Val Gln Glu Ala Thr Thr Ser Lys Leu Leu Pro Phe AspSer 1595 1600 1605 Leu Ser Arg Tyr Ile Phe Glu Lys Pro Arg Ile Val GlyGly Lys 1610 1615 1620 Ala Ala Ser Phe Thr Ile Pro Ala Asn Ser Asp AlaPhe Leu Pro 1625 1630 1635 Cys Glu Ala Val Gly Asn Pro Leu Pro Thr IleHis Trp Thr Arg 1640 1645 1650 Val Ser Gly Leu Asp Leu Ser Arg Gly AsnGln Asn Ser Arg Val 1655 1660 1665 Gln Val Leu Pro Asn Gly Thr Leu SerIle Gln Arg Val Glu Ile 1670 1675 1680 Gln Asp Arg Gly Gln Tyr Leu CysSer Ala Ser Asn Leu Phe Gly 1685 1690 1695 Thr Asp His Leu His Val ThrLeu Ser Val Val Ser Tyr Pro Pro 1700 1705 1710 Arg Ile Leu Glu Arg ArgThr Lys Glu Ile Thr Val His Ser Gly 1715 1720 1725 Ser Thr Val Glu LeuLys Cys Arg Ala Glu Gly Arg Pro Ser Pro 1730 1735 1740 Thr Val Thr TrpIle Leu Ala Asn Gln Thr Val Val Ser Glu Ser 1745 1750 1755 Ser Gln GlySer Arg Gln Ala Val Val Thr Val Asp Gly Thr Leu 1760 1765 1770 Val LeuHis Asn Leu Ser Ile Tyr Asp Arg Gly Phe Tyr Lys Cys 1775 1780 1785 ValAla Ser Asn Pro Gly Gly Gln Asp Ser Leu Leu Val Lys Ile 1790 1795 1800Gln Val Ile Ala Ala Pro Pro Val Ile Leu Glu Gln Arg Arg Gln 1805 18101815 Val Ile Val Gly Thr Trp Gly Glu Ser Leu Lys Leu Pro Cys Thr 18201825 1830 Ala Lys Gly Thr Pro Gln Pro Ser Val Tyr Trp Val Leu Ser Asp1835 1840 1845 Gly Thr Glu Val Lys Pro Leu Gln Phe Thr Asn Ser Lys LeuPhe 1850 1855 1860 Leu Phe Ser Asn Gly Thr Leu Tyr Ile Arg Asn Leu AlaSer Ser 1865 1870 1875 Asp Arg Gly Thr Tyr Glu Cys Ile Ala Thr Ser SerThr Gly Ser 1880 1885 1890 Glu Arg Arg Val Val Met Leu Thr Met Glu GluArg Val Thr Ser 1895 1900 1905 Pro Arg Ile Glu Ala Ala Ser Gln Lys ArgThr Glu Val Asn Phe 1910 1915 1920 Gly Asp Lys Leu Leu Leu Asn Cys SerAla Thr Gly Glu Pro Lys 1925 1930 1935 Pro Gln Ile Met Trp Arg Leu ProSer Lys Ala Val Val Asp Gln 1940 1945 1950 Gly Ser Trp Ile His Val TyrPro Asn Gly Ser Leu Phe Ile Gly 1955 1960 1965 Ser Val Thr Glu Lys AspSer Gly Val Tyr Leu Cys Val Ala Arg 1970 1975 1980 Asn Lys Met Gly AspAsp Leu Ile Leu Met His Val Ser Leu Arg 1985 1990 1995 Leu Lys Pro AlaLys Ile Asp His Lys Gln Tyr Phe Arg Lys Gln 2000 2005 2010 Val Leu HisGly Lys Asp Phe Gln Val Asp Cys Lys Ala Ser Gly 2015 2020 2025 Ser ProVal Pro Glu Ile Ser Trp Ser Leu Pro Asp Gly Thr Met 2030 2035 2040 IleAsn Asn Ala Met Gln Ala Asp Asp Ser Gly His Arg Thr Arg 2045 2050 2055Arg Tyr Thr Leu Phe Asn Asn Gly Thr Leu Tyr Phe Asn Lys Val 2060 20652070 Gly Val Ala Glu Glu Gly Asp Tyr Thr Cys Tyr Ala Gln Asn Thr 20752080 2085 Leu Gly Lys Asp Glu Met Lys Val His Leu Thr Val Ile Thr Ala2090 2095 2100 Ala Pro Arg Ile Arg Gln Ser Asn Lys Thr Asn Lys Arg IleLys 2105 2110 2115 Ala Gly Asp Thr Ala Val Leu Asp Cys Glu Val Thr GlyAsp Pro 2120 2125 2130 Lys Pro Lys Ile Phe Trp Leu Leu Pro Ser Asn AspMet Ile Ser 2135 2140 2145 Phe Ser Ile Asp Arg Tyr Thr Phe His Ala AsnGly Ser Leu Thr 2150 2155 2160 Ile Asn Lys Val Lys Leu Leu Asp Ser GlyGlu Tyr Val Cys Val 2165 2170 2175 Ala Arg Asn Pro Ser Gly Asp Asp ThrLys Met Tyr Lys Leu Asp 2180 2185 2190 Val Val Ser Lys Pro Pro Leu IleAsn Gly Leu Tyr Thr Asn Arg 2195 2200 2205 Thr Val Ile Lys Ala Thr AlaVal Arg His Ser Lys Lys His Phe 2210 2215 2220 Asp Cys Arg Ala Glu GlyThr Pro Ser Pro Glu Val Met Trp Ile 2225 2230 2235 Met Pro Asp Asn IlePhe Leu Thr Ala Pro Tyr Tyr Gly Ser Arg 2240 2245 2250 Ile Thr Val HisLys Asn Gly Thr Leu Glu Ile Arg Asn Val Arg 2255 2260 2265 Leu Ser AspSer Ala Asp Phe Ile Cys Val Ala Arg Asn Glu Gly 2270 2275 2280 Gly GluSer Val Leu Val Val Gln Leu Glu Val Leu Glu Met Leu 2285 2290 2295 ArgArg Pro Thr Phe Arg Asn Pro Phe Asn Glu Lys Ile Val Ala 2300 2305 2310Gln Leu Gly Lys Ser Thr Ala Leu Asn Cys Ser Val Asp Gly Asn 2315 23202325 Pro Pro Pro Glu Ile Ile Trp Ile Leu Pro Asn Gly Thr Arg Phe 23302335 2340 Ser Asn Gly Pro Gln Ser Tyr Gln Tyr Leu Ile Ala Ser Asn Gly2345 2350 2355 Ser Phe Ile Ile Ser Lys Thr Thr Arg Glu Asp Ala Gly LysTyr 2360 2365 2370 Arg Cys Ala Ala Arg Asn Lys Val Gly Tyr Ile Glu LysLeu Val 2375 2380 2385 Ile Leu Glu Ile Gly Gln Lys Pro Val Ile Leu ThrTyr Ala Pro 2390 2395 2400 Gly Thr Val Lys Gly Ile Ser Gly Glu Ser LeuSer Leu His Cys 2405 2410 2415 Val Ser Asp Gly Ile Pro Lys Pro Asn IleLys Trp Thr Met Pro 2420 2425 2430 Ser Gly Tyr Val Val Asp Arg Pro GlnIle Asn Gly Lys Tyr Ile 2435 2440 2445 Leu His Asp Asn Gly Thr Leu ValIle Lys Glu Ala Thr Ala Tyr 2450 2455 2460 Asp Arg Gly Asn Tyr Ile CysLys Ala Gln Asn Ser Val Gly His 2465 2470 2475 Thr Leu Ile Thr Val ProVal Met Ile Val Ala Tyr Pro Pro Arg 2480 2485 2490 Ile Thr Asn Arg ProPro Arg Ser Ile Val Thr Arg Thr Gly Ala 2495 2500 2505 Ala Phe Gln LeuHis Cys Val Ala Leu Gly Val Pro Lys Pro Glu 2510 2515 2520 Ile Thr TrpGlu Met Pro Asp His Ser Leu Leu Ser Thr Ala Ser 2525 2530 2535 Lys GluArg Thr His Gly Ser Glu Gln Leu His Leu Gln Gly Thr 2540 2545 2550 LeuVal Ile Gln Asn Pro Gln Thr Ser Asp Ser Gly Ile Tyr Lys 2555 2560 2565Cys Thr Ala Lys Asn Pro Leu Gly Ser Asp Tyr Ala Ala Thr Tyr 2570 25752580 Ile Gln Val Ile 2585 17 5551 DNA Mus musculus 17 tctagaagtaaaatgatcct gagtagcgat cctgggaaaa tacgtactct aacacactgc 60 aatcatctctctgtggtttg ctggagctga ggtctggaag gctcgacctt ggttagaaat 120 aacctaccgaatacagagct atgacgttag tctggaagga gctttggaag aatgacaagc 180 tgtagctgcccagaacatac tagatgccat atttccaagg caagtgtcca catgcggaca 240 tcttaagaatatggttgtct ctgcagtgct aaggaccttg ttcgtgccac acaggtctcc 300 agggttagtgctaactctga ctgcttgact ctttaattct accttgatca ttaatgacta 360 gaaatcacttggtgattagc aactggatat ggaatattac taatttgtac ccaagccagg 420 ccacctcagctttggcagct ccattcattc tgtggagccc agtcacgtgg gtttgaatca 480 actgtactgtttctacttac aagacgcatt acctgagatg agtcattttt cttcacaagt 540 ctttttagaagagtcaatta gacatattct gatgaagtaa gcatataaag tgagagcagc 600 atgaatgtgttccatgtatg ctcatggatg ctattataat gtggaaataa actgacttta 660 aaaaaaaaagcttatgatac ttgtcacaga gtaaatcttc cataaatatc atctgcattt 720 ataaattattttcataatcc atcaattaaa aacctttaga aattttgtta acacaaagat 780 ccctaggcccctgccctagg atggtctgta tggtgggcct gagagatgga gcttaagaac 840 ttacttgctccaggagcaca tcttcagaac atctgcctca aaacatttat cccaaatgct 900 catcaaaggctcactcacat gtgcttcaac cacagggatt aaacagtcat tttagtcaca 960 tttctcaaacggtggaagcc tgctagagga acaggatgta tcaggataac atccaacctt 1020 acaaaaggatgtcataaccc tcaccacaac aaacaacaac gacaacaaac ccataaaaat 1080 tatcacggcaaatgaactaa gccatatgca gaaaaagtat tatatgttct cattgtgggg 1140 tgtttttccttaatagtcaa atatgcagaa tatagacaaa gatggtttat gcaagtgggg 1200 atggcgaaggatacttgtag attagaggac acaaagcaac aactacagag tgaagtaatc 1260 cagagacttaatgtataata tgaggactgt atttaataat tctatttaag atacacagca 1320 aacgagtgtatcttactaac acacacactt acatagagag aataaagtga tagatacgtt 1380 tgttttatcttcatgtagct gataatttca tattgtacac ctcaaacata gataaccaac 1440 aaagaggaagaggataggtg cctctcccag ggcggaagag tacattcgaa agtcagacac 1500 cattgtgtagatgtaccaca tggaggagct agagaaagta gccaaggagc taaagggatc 1560 tgcaaccctataggtggaac aacattatga gctaaccagt accccggagc tcttgactct 1620 agctgcatatatatcaaaag atggcctaat cggccatcac tggaaagaga ggcccattgg 1680 acttgcaaactttatatgcc ccagtacagg ggaataccag ggccaaaaag ggggagtggg 1740 tgggcaggggagtgggggtg ggtggatatg ggggactttt ggtatagcat tggaaatgta 1800 aatgagttaaatacctaata aaaaatggaa aaaaaaaaaa aaaaaaaaaa aaaggaaggt 1860 cagacacctcacttcactgc tatctcaact tgcaaacaga aggggagtca caaacccagg 1920 acaaaccacagtgattgaag cgtctttgaa tgttattgct gttgttgtta ccaccatcat 1980 tagcatatattcattgtgaa aacttacggg gtctatgaca tgttttttta ttcaagtata 2040 tcacatgctgtcagcatatt tggcaccact accagcccca gccccctttg ccccgccccc 2100 aacacacacacacacacaca cacacacaca cacacacaca cacacacaca cacacacacc 2160 tttaccttctcctgggcatc atctgctcac tcacccaccc aagcttaatc cttttccttc 2220 cctgcaatagtacctctcct atttttatgt ctaggttccc cctccccctg ttaggagatg 2280 ggagaggtcacgaaaggaaa gaatttgtag cccctgagcc agcccgggcc acagagcctg 2340 ccaccagacaggaaaagccc agggcttacc agcacaggag gagcaaactc gcaggcgagc 2400 ctgggttggcgctggtggtc ccgggtcgat ggcccgccca ttcccagaag ccgaggctat 2460 agctgcgtcacctgccccgc cctcctcccg agtgaagacc cctagaggct gagcagaccc 2520 caaaggcggtgcaattccat tggcccaagg cagaggtgag cggctgctaa tcccctcggg 2580 aagtgaagggacccagagag tctggtagat gtgggagctg gggttcaggg cgagacagag 2640 ggtgggatgggcagaagggt ccaggaaaag gaaagtactg gaggggagtt gggacaaaag 2700 cagcgaccaagggaacatcg cttcagtgac tgaagccagg caaaaggagc gggaaggatt 2760 atatgtagcctgggacgctt tcataaacac tgatgacgtg tttgtgcaaa gcaagcaatt 2820 tgaggagaaacgcctgggac gtcggaaaga aggagtgatc gattagtact tgtaagttta 2880 ggtgagtttgagaactaact aacctatact attgagggag aaggaagagc attccagcag 2940 cagcagcagcagcagcaatc agataaagga aagctttggt tagtttggaa atgtatgata 3000 ccattaaaataacagaagcg cctccagttc tctgaagagt cagtccccca gctagtgaag 3060 actaagcctactaagccttt tgctcccgtt ggaagcaaag aacgttcctt caatcaggtg 3120 aaggctctcctcagaagatt tcctgtctct gcttatgtta caagaggatt caaaagcaag 3180 acagaagagctcaggtattg ccaactcttt tgttaaatac agtttgaggc ttaagtgtac 3240 gggaactcatgtggtattca tttacggctc tcttctctta taactaactc ttaaggtgca 3300 tatagtctcttctgtttccc agctaccttg taccatcttt gtttatctaa taatagcaag 3360 ctcatctgctttttaatcat cacgcagaga gtattcaaaa atattcagtg atgtaacagt 3420 gacagtgtaggcatagaagt aatcattagt aaatcttaat ttgggttaaa ctcattcata 3480 acagctccaggttgggaggg atcactgagc cttcgccacg tgcgggttaa agatattttc 3540 taacaagagaagcagaattc ttccttggcc atgctcccca tcactgtgtc agtaagcaga 3600 ggggtgtttccaagcagaga aagagcagac agtgttatgc ctgcaaagtc agagactcag 3660 ccctcccagctggtcagttt actgtcctcc cggtcattag ttggctctga aaaggcccat 3720 gtgtccttattggcaaggac ttgcagacat gctagaaaga aatttgacct ttttttctag 3780 tgggttattacagctgtaaa agtattttgg aaggttaagc caaataaata aaacacatat 3840 taaataatacaatgttacaa aaattgatca tataaagaag tacattcata aatgcaatgt 3900 gaaaaatatatataattttt atctatttac tggtgcaaag ttttctaaat tgcacatgta 3960 ctatttttatatttataaaa atatttttaa aatgtatata aaagtgtaaa aggctcttgg 4020 tcaaacaagagagttaaatt tacaaacttt aattgtcccg ataacattat tatgatctct 4080 aatgacagggatcctgcttt tcattgggaa atgagaagct atgaagatat gtttacaata 4140 ataagcccatttagtgataa agtccaatgg gaagctagca cacactggtt tataaagaga 4200 acagtttcctgagtctatgc aagtttacac tctagggaat aagagttcct ctttctccag 4260 atttcactagcatttgttgt catcatttat cttcttgatg atgagcatta taagtggaat 4320 aagataggatctcaaaggaa tgtcaatttg gatgccctga acaatctttc aggtctttct 4380 ttcagttcactagtctattc atttattgga taattggggg atggtgttaa tttttttgca 4440 gttcttatggaattccaaaa aacaaaaaac aaacaaacaa acaaaaaacc tctgaaacta 4500 gaactaccaatccattactg ggtatgtaac aaagagaaat ctgcacagaa tttattgcta 4560 cattgttcattattcacgac agccaagaat gtggaaccaa cttacgtagc cgtcaaaata 4620 tgaacggataaagaaaatgt ggaaatgtgt acaacagagt cccatgtggc cataaaagag 4680 tgaaatcatgacatatgcag gaaatggatg caactggaaa tcaattgggc taatcaaaac 4740 aagacagactcaaaaaggaa acaccgtgta gcttctctga caaacagaag ctagatttac 4800 acttgtacgtgcgcatgtgt gtttagaatt ttatttagtt atacactatt ctaatctgtg 4860 agtgtgtataaaggcatgca tgtaaagcaa aaacaagcta gctggggtgg gtaggagaga 4920 aagcaatgagaggagttaat aagaacgaag catagtaaca taggtgccag gatgaaatgc 4980 attaatttgtatgctaacta aaccacagac aggaggcaca cgttcaaacc agggtgaaat 5040 cccagcacagagaaggggaa gtagacacaa agtttcgcca ctaaccaaga agccatttgc 5100 agttgctgcctgctgggagg ggcgttccag ttttctccag tctgacactg tgtataacaa 5160 ccagttgacaatacaaagtt ggcatgatgg atggtttttg tgctattttt catttttttt 5220 cttactgttttgttgttgtg gtggttgttg tggtggtggc tgtggttttc atttgtttct 5280 tttgagagagagaaggaaca tgaaattggg tgggtaggaa gctggaaacg atctggaaga 5340 agttggggaaagagaaaaat tgtatggagc atatttaaac aaacaaacaa acaaacaaaa 5400 ggttcattttgccacaaaaa ggtgtgaatt aaattaacca gttacgactc ttaaagaaaa 5460 tattcccaattattcccaga gttgctatgt atgctgtgcc taggactttg cttgaactgg 5520 ccctataactctggtgtggt gtcttttcag g 5551 18 4610 DNA Mus musculus 18 cacagaccttcctcttctaa cctctctccc ccatcttgtt gcttcatccc agacttcaac 60 accagcaagcacactctgct aatgcaaggg ctgctcctgt caggacaaca aggaggctga 120 aggcagacccacacgtttcc aactgctcct gagagtcaat ccccctagac tcatctatag 180 caggaaacctgctgtgatct ccatttcttc tctgaccaca tccccaagtt atcacaagga 240 gtttttcctcaaacctttcc tctccagcaa accccttcag ctccttgggt actttctcta 300 gccccttcattgggaaccct gtgctccatc caatggatgg ctgtgagcat ccacttctgt 360 atagaatcttggtcagtgca gtcttttgta tcctcaagaa cactgggtct gaaaatttta 420 acccaaagaactgttttttg ttatgattgc tgcaatctct ttcaattcca ataaagagta 480 agcatctcattcctttgtct cctcctttca gtaccaccct gcctttgctg cctttctcaa 540 agaatcaataaaaccaaagt gatatagatt catggcattc ctctaactgc tacatccact 600 ccagtagtatctcacttggc aggtgtaaaa gcctggaagc agtcacgagg cagtttcaca 660 gaaacttagcctcctggaac cttggcattc ccatagctag aatgccccag atttgtccct 720 gagatattgtggtgggtctt gcatgctttc ttgcagtatt ttactggata agagttagaa 780 atctcagggcgagcttagca aaagtatacc tagaatcttc atgacagtca ggtattgcaa 840 actacattgcatattagaag aaagttggta aattcttctg acaaatggag attccctaca 900 gataacttaaaagaacagct aagtcacact catatgcaag aatttaccaa ggcctaggaa 960 agggggggggggtactgctt tattcatgat aaggtctgct agagcagaac cccctggtgc 1020 tagctttcacaaggttcaaa ggtgtagcat aaattgtgac tagagtgtga aatctttacc 1080 tgtcattagctgactctagg cagagctgtt ttatctttac tgtaaacatt acctggttcc 1140 tgtcagtcctttgaaggcat tcctctgttt tgtgacagat acttctatgt acctcgcctg 1200 ctgtgacaccctactccttt gttttctgta ttatataagc ctggtgttcc ctttgtgaaa 1260 aattacatccagatacagca ctcccttgtg tctgtgtcct tttgtcattt ctggccaact 1320 ccatgcccacctgccagaac ccctagtctt ttccacagat tgagggaggc cgactgagcc 1380 tggtccatggcatctaacca ctgtcagctc actgttggtg actacctcaa ggtacaagct 1440 ccattactaatgaaacaaaa ttagataagt gtgggtccag gaagcaggtt gtacaccctg 1500 tctgaatgaacattatgaaa tgactgaaat aagttaaccc atctcttcct cgtttgctaa 1560 tatagcaaataaaccgagtt tctgagctgc tgctggtgtg tctccatcag agggcagagc 1620 cagtctgatcctagctttcc tgtatgtgtg tccattgttt cttcagttcc tgttgcccca 1680 ttaggaaatcctaagccatg aaagccatga atctgggaat gacttttcta agaaatgcca 1740 cgtgaaccttgcgtttcaac gttttgcctg taaacaagat atatggtgcg cagtttataa 1800 tcataataagctttgaaata atatataact ccattctcat tctgcttcca cgctgagcat 1860 cctgtttccccagggaccac aagagcattt gaaaagtagt gatttatgac ctgctttgtt 1920 ctgttactataaaagcttca tgaaagggca gccatgttga aacatggaac ttggggtgac 1980 ctgtatctgtgttcctgggt cgtgctcact catatttgtc tccagaataa atgagtttat 2040 caacttcgaggaaaaagttg tgtgtttgta tagcacgccc gtggagtccc accattctac 2100 ttcctgtaatctgtatatgg tagaaaaagt taatttatgt gattcttcca actccaaata 2160 tttcaaatcttttagcccct cagcctggga tttctttgac taagtctatt gatttggaag 2220 atctcagtggttaggatttg cagtcatgat gttcatacgt caggctaagc tgaaaaatat 2280 gacaaatgaaatgtcaaatg tcatgtgcct gggaatgtga gtgttagggg gttttaaaga 2340 aacaaatacctactctaaat agttaataag tcccatggtt ctattctagt tttgaataat 2400 gttccctagtatacagcaat ttaatttgaa atgaatagct tcttatcttg accaatctca 2460 gtgacttcatccgtcccaag tcatgttttc atattcataa ggataggtct cattcaacca 2520 catgtttatcatttgggatc tgcatttttc tgatgcaaaa tgatttattc ttccagagca 2580 ctggaattgggttgaatcat cttataacgg ccaaaactaa atgcttctgt gctaaacaga 2640 gagttacaagacctttttat gtggatggca gcattttagt catccttatg acagaatgtc 2700 agagtggagctcccactggg ggaggggctg gtccttggca ggattctctt ggaacatcac 2760 acaaagaaattccaaattat gaaatgcaca tgatccatcc agaatgtgac ttttgactct 2820 tgaacatgagcttttaaagt acgtttggct gttcagacct tgactttgag gtgaaggaaa 2880 gctcgccaactcctttttat atgtaacaca atatatcaag atctaatgtg agacagtatg 2940 ccagtcccaagatctgtcaa tatgactgaa gacacattgc gatgttatca ctaaggcagg 3000 agaaggcaagctacagtgaa gcccagttca ctataaagct ttatgagaaa ttagataaga 3060 agggtttctaatttttaaat tttttttatt agatattttc ttcatttaca tttcaaatgc 3120 tatcccaaaagtcccctata ctcccccctc accctgctcc cctacccacc cactcccatt 3180 tcttggccctggttacttgt gatagtggtc atatgatcca ccaagcttta catgctcact 3240 atctggtctattgcaagaat ggctgccgag ctgatgcagt cagatacaga cacctacagc 3300 caaacagtggaaggaacttg gggactctta tggaagaaaa ggaggaaggg ttatgggccc 3360 cggatggggaaaggaactcc acaggaagac caacatactt ggtcaactaa cctggaccct 3420 tggggctctcagagtctgaa ccaccaacca tagaacattc atgggctgta cccaggcctc 3480 tccactcatatgtaacagat atgtggcttg gccttcatct gggtcctgaa caactagatg 3540 ggggttaggggtggggatgg gggttatctc aaaagctgtt gcctgtatgt gggatatgtt 3600 cttactgagctgcctagtct ggcctcagtg ggagaggaag cacctagctt tagccttgta 3660 aagacttgaagttctgaggt gtcggtggag ggtatactca gggaggccct cacctgctag 3720 gaagagaagaggagggggaa gacttggggg agggggcagt gagcaggttg gtaaaatgaa 3780 taagaaaaaaaaaataaaaa taattaaaaa aaaaaaagaa tggctgctga gccctactct 3840 aaaaccattgcatccccccc ccccaatcat tcagtgacta cgaattaaaa tcattgatac 3900 taacaatagatgtaggaaac tattgttaac ttctttgtga ccacgagtgg tatttggaac 3960 cttttttattgaagctttca cacagagcct tgttctttca tttccctgta catgcatgta 4020 gcttaatgatgttcagtgaa ttaaaaataa caatgaagaa taaagacaac tgtattttaa 4080 ggattcttcgtatatattta aaaatctaag gtggtcacct ggaagaaatg tcttcagttt 4140 ttctatatatgtttactcta tcgtatgtta attaattata tgcaataatt cataaaatct 4200 acaacatagtatgtaactta taagaaagta aaacattcat gaaattgtga aggttacttt 4260 tccttaccctcagaaacact gggtttgaat aattcttatt ttggtatcag tgaagaattt 4320 gaaagaatgtaataacctac taaggcaaac atagaagttg aaattaaaaa gagtagacag 4380 gagaagtaataaggcaaata atgaatattt gctttaaata gttcttaatg tatcatctaa 4440 ctagggtgtgattctccaga cttgactcca tccaaaatat ccaaaatgac tctaaccaca 4500 gtcattgaaacaatgtgttg aaaataataa acatttccta cttgaaaatt cagatttctc 4560 ctactttgctttttattgct gtgataagca ccatgaccaa agcagcttat 4610 19 424 DNA ArtificialSequence primer 19 taagcctttt gctcccgttg gaagcaaaga acgttccttcaatcaggtga aggctctcct 60 cagaagattt catgtctcag cttatgttac aagaggattcaaaagcaaga cagaagagct 120 caggtatagc caactctttt gttaaataca gtatgaggcttaagtgtacg gcaactcatg 180 tggtattcat ttgcggctct cttctcttat aactaactcttaaggtgcat atagtctctt 240 ctgtttccca gctaccttgc accatctttg tttatctaataatagcaagc tcatctgctt 300 tttaatcatc acgcagagag tattcaaaaa tattcagtgatgtaacagtg acagtgtagg 360 catagaagta atcattagta aatcttaata tgggttaaactcattcataa cagctccagg 420 ttgg 424 20 11962 DNA Mus musculusmisc_feature (1)..(11962) ′n′ can be any nucleotide ′a′, ′c′, ′g′ or′t′. 20 tttggaacca acccagatgc ccctcaacag agaaatgggc cagaaaatgtggtccattta 60 tccaatggaa tactactcaa cttattaaaa acaacgactt tcataaaatttttaggcaaa 120 tgnatggtct gnaggatctt gagtgaggta acccaatcac aaaagaacactcatggtatg 180 cactcactga taagtggcta tttgtctatg gagtgattta aaagggaagaagacacatag 240 ctttttgtgt gtataatatt aagatggaaa tttgccagtg ctgtttggcttatgagtgaa 300 tcttgtttca gtggattacc ggaagaaaat aataagtgaa ctgtaggaagaagtagttaa 360 tcaaggtgac aaagtatcct gacacattgg gaaaagacca cagtccaggaaactgagtct 420 taaggattca tattaactcc agttccccat gtgcagctct gagactttggcagatcagac 480 acttaacttc accagcttcc tacacagagc agttactatc cttgccttcacacatggagt 540 gtgccattaa gtgcctgaac atgagtctga cttgttaata atctttaaaatccaattgtg 600 tgtaaagtat gtgaccaaag agcatggtca tgctattaac ctttgatgttctatggactc 660 ttaattttat ggtagaaatg tcaacaagct tgtggaggct ggaagatacaaggcttaaga 720 ggatggcctt tcagttttga aagtaattca gtatgtgttc tggcatcccttttcctaaag 780 caatttaacc ccccaagtag gcataatttt aatgcttact tcatcagaatatatctaatt 840 gactcttcta aaaagacttt ggtatgcata ggatctaaat gtaaatgtgatttactgaca 900 taataaatag gagaaactga gctagaatag gtataaaata tgtgctggctttctaatagg 960 tcttataggt tatataagag gtgggaaagg aatatttgaa acatctagaagtaaaatgat 1020 cctgagtagc gatcctggga aaatacgtac tctaacacac tgcaatcatctctctgtggt 1080 ttgctggagc tgaggtctgg aaggctcgac cttggttaga aataacctaccgaatacaga 1140 gctatgacgt tagtctggaa ggagctttgg aagaatgaca agctgtagctgcccagaaca 1200 tactagatgc catatttcca aggcaagtgt ccacatgcgg acatcttaagaatatggttg 1260 tctctgcagt gctaaggacc ttgttcgtgc cacacaggtc tccagggttagtgctaactc 1320 tgactgcttg actctttaat tctcccttga tcattaatga ctagaaatcacttggtgatt 1380 agcaactgga tatggaatat tacttaattt gtacccaagc caggccacctcagctttggc 1440 agctccattc attctgtgga gcccagtcac gtgggtttga atcaactgtactgtttctac 1500 ttacaagacg cattacctga gatgagtcat ttttcttcac aagtctttttagaagagtca 1560 attagacata ttctgatgaa gtaagcatat aaagtgagag cagcatgaatgtgttccatg 1620 tatgctcatg gatgctatta taatgtggaa ataaactgac tttaaaaaaaaaagcttatg 1680 atacttgtca cagagtaaat cttccataaa tatcatctgc atttataaattattttcata 1740 atccatcaat taaaaacctt tagaaatttt gttaacacaa agatccctaggcccctgccc 1800 taggatggtc tgtatggtgg gcctgagaga tggagcttaa gaacttacttgctccaggag 1860 cacatcttca gaacatctgc ctcaaaacat ttatcccaaa tgctcatcaaaggctcactc 1920 acatgtgctt caaccacagg gattaaacag tcattttagt cacatttctcaaacggtgga 1980 agcctgctag aggaacagga tgtatcagga taacatccaa ccttacaaaaggatgtcata 2040 accctcacca caacaaacaa caacgacaac aaacccataa aaattatcacggcaaatgaa 2100 ctaagccata tgcagaaaaa gtattatatg ttctcattgt ggggtgtttttccttaatag 2160 tcaaatatgc agaatataga caaagatggt ttatgcaagt ggggatggcgaaggatactt 2220 gtagattaga ggacacaaag caacaactac agagtgaagt aatccagagacttaatgtat 2280 aatatgagga ctgtatttaa taattctatt taagatacac agcaaacgagtgtatcttac 2340 taacacacac acttacatag agagaataaa gtgatagata cgtttgttttatcttcatgt 2400 agctgataat ttcatattgt acacctcaaa catagataac caacaaagaggaagaggata 2460 ggtgcctctc ccagggcgga agagtacatt cgaaagtcag acaccattgtgtagatgtac 2520 cacatggagg agctagagaa agtagccaag gagctaaagg gatctgcaaccctataggtg 2580 gaacaacatt atgagctaac cagtaccccg gagctcttga ctctagctgcatatatatca 2640 aaagatggcc taatcggcca tcactggaaa gagaggccat tggacttgcaaactttatat 2700 gccccagtac aggggaatac cagggccaaa aagggggagt gggtgggcaggggagtgggg 2760 gtgggtggat atgggggact tttggtatag cattggaaat gtaaatgagttaaataccta 2820 ataaaaaatg gaaaaaaaaa aaaaaaaaaa aaaaaaggaa ggtcagacacctcacttcac 2880 tgctatctca acttgcaaac agaaggggag tcacaaaccc aggacaaaccacagtgattg 2940 aagcgtcttt gaatgttatt gctgttgttg ttaccaccat cattagcatatattcattgt 3000 gaaaacttac ggggtctatg acatgttttt ttattcaagt atatcacatgctgtcagcat 3060 atttggcacc actaccagcc ccagccccct ttgccccgcc cccaacacacacacacacac 3120 acacacacac acacacacac acacacacac acacacacac acctttaccttctcctgggc 3180 atcatctgct cactcaccca cccaagctta atccttttcc ttccctgcaatagtacctct 3240 cctattttta tgtctaggtt ccccctcccc ctgttaggag atgggagaggtcacgaaaga 3300 aaggaatttg tagcccttga gccagcccgg gccacagagc ctgccaccagacaggaaaag 3360 cccagggctt accagcacag gaggagcaaa ctcgcaggcg agcctgggttggcgctggtg 3420 gtcccgggtc gatggcccgc ccattcccag aagccgaggc tatagctgcgtcacctgccc 3480 cgccctcctc ccgagtgaag acccctagag gctgagcaga ccccaaaggcggtgcaattc 3540 cattggccca aggcagaggt gagcggctgc taatcccctc gggaagtgaagggacccaga 3600 gagtctggta gatgtgggag ctggggttca gggcgagaca gagggtgggatgggcagaag 3660 ggtccaggaa aggaaagtac tggaggggag ttgggacaaa agcagcgaccaagggaacat 3720 cgcttcagtg actgaagcca ggcaaaagga gcgggaagga ttatatgtagcctgggacgc 3780 tttcataaac actgatgacg tgtttgtgca aagcaagcaa tttgaggagaaacgcctggg 3840 acgtcggaaa gaaggagtga tcgattagta cttgtaagtt taggtgagtttgagaactaa 3900 ctaacctata ctattgaggg agaaggaaga gcattccagc agcagcagcagcagcagcaa 3960 tcagataaag gaaagctttg gttagtttgg aaatgtatga taccattaaaataacagaag 4020 cgcctccagt tctctgaaga gtcagtcccc cagctagtga agactaagcctactaagcct 4080 tttgctcccg ttggaagcaa agaacgttcc ttcaatcagg tgaaggctctcctcagaaga 4140 tttcctgtct ctgcttatgt tacaagagga ttcaaaagca agacagaagagctcaggtat 4200 tgccaactct tttgttaaat acagtttgag gcttaagtgt acgggaactcatgtggtatt 4260 catttacggc tctcttctct tataactaac tcttaaggtg catatagtctcttctgtttc 4320 ccagctacct tgtaccatct ttgtttatct aataatagca agctcatctgctttttaatc 4380 atcacgcaga gagtattcaa aaatattcag tgatgtaaca gtgacagtgtaggcatagaa 4440 gtaatcatta gtaaatctta atttgggtta aactcattca taacagctccaggttgggag 4500 ggatcactga gccttcgcca cgtgcgggtt aaagatattt tctaacaagagaagcagaat 4560 tcttccttgg ccatgctccc catcactgtg tcagtaagca gaggggtgtttccaagcaga 4620 gaaagagcag acagtgttat gcctgcaaag tcagagactc agccctcccagctggtcagt 4680 ttactgtcct cccggtcatt agttggctct gaaaaggccc atgtgtccttattggcaagg 4740 acttgcagac atgctagaaa gaaatttgac ctttttttct agtgggttattacagctgta 4800 aaagtatttt ggaaggttaa gccaaataaa taaaacacat attaaataatacaatgttac 4860 aaaaattgat catataaaga agtacattca taaatgcaat gtgaaaaatatatataattt 4920 ttatctattt actggtgcaa agttttctaa attgcacatg tactatttttatatttataa 4980 aaatattttt aaaatgtata taaaagtgta aaaggctctt ggtcaaacaagagagttaaa 5040 tttacaaact ttaattgtcc cgataacatt attatgatct ctaatgacagggatcctgct 5100 tttcattggg aaatgagaag ctatgaagat atgtttacaa taataagcccatttagtgat 5160 aaagtccaat gggaagctag cacacactgg tttataaaga gaacagtttcctgagtctat 5220 gcaagtttac actctaggga ataagagttc ctctttctcc agatttcactagcatttgtt 5280 gtcatcattt atcttcttga tgatgagcat tataagtgga ataagataggatctcaaagg 5340 aatgtcaatt tggatgccct gaacaatctt tcaggtcttt ctttcagttcactagtctat 5400 tcatttattg gataattggg gggatggtgg taattttttt gcagttcttatggaattcca 5460 aaaaacaaaa aacaaaccaa ccaaccaaaa acctctgaaa ctagaactaccaatccatta 5520 ctgggtatgt aacaaagaga aatctgcaca gaatttattg ctacattgttcattattcac 5580 gacagccaag aatgtggaac caacttacgt agccgtcaaa atatgaacggataaagaaaa 5640 tgtggaaatg tgtacaacag agtcccatgt ggccataaaa gagtgaaatcatgacatatg 5700 caggaaatgg atgcaactgg aaatcaattg ggctaatcaa aacaagacagactcaaaaag 5760 gaaacaccgt gtagcttctc tgacaaacag aagctagatt tacacttgtacgtgcgcatg 5820 tgtgtttaga attttattta gttatacact attctaatct gtgagtgtgtataaaggcat 5880 gcatgtaaag caaaaacaag ctagctgggg tgggtaggag agaaagcaatgagaggagtt 5940 aataagaacg aagcatagta acataggtgc caggatgaaa tgcattaatttgtatgctaa 6000 ctaaaccaca gacaggaggc acacgttcaa accagggtga aatcccagcacagagaaggg 6060 gaagtagaca caaagtttcg ccactaacca agaagccatt tgcagttgctgcctgctggg 6120 aaggggcgtt ccagttttct ccagtctgac actgtgtata acaaccagttgacaatacaa 6180 agttggcatg atggatggtt tttgtgctat ttttcatttt ttttcttactgttttgttgt 6240 tgtggtggtt gttgtggtgg tggctgtggt tttcatttgt ttcttttgagagagagaagg 6300 aacatgaaat tgggtgggta ggaagctgga aacgatctgg aagaagttggggaaagagaa 6360 aaattgtatg gagcatattt aaacaaacaa acaaacaaac aaaaggttcattttgccaca 6420 aaaaggtgtg aattaaatta accagttacg actcttaaag aaaatattcccaattattcc 6480 cagagttgct atgtatgctg tgcctaggac tttgcttgaa ctggccctataactctggtg 6540 tggtgtcttt tcaggatgca gaagagaggc agggaagtca gctgcttgctgatctccctc 6600 actgccatct gcctggtggt cacccctggg agcagggtct gtcctcgccgatgtgcctgc 6660 tatgtgccca cagaggtgca ctgtacattt cgggacctga cctccatcccagacgggcat 6720 cccagccaat gtggaacgag tcaatttagg gtgtgtggac cttgcctgatctccttctca 6780 gagagggacc actgattttc ctggtacttt gccccccaaa cacctgtgattacttttaat 6840 agttttcttc taaaatgggt tcatacaaac cttatattgt ggagacaatgaacattttat 6900 cccaatagtc ttttactaga acttgaagcc cctcttagtt gtttgggagcctcataatta 6960 tggggcagct ttattctgaa tgaattttaa atgaaaaaga tacagtttctgttaacaatc 7020 attatgatac caaggaagag gaattgtcat tgaatatttt aaaaaagcatttcttttgca 7080 atttataaat acccattaca aaatggctta cttaaaatac ttgccttactaaatctgaca 7140 aattatggtg atattttgaa ggtttatgaa aatttgttta tgtgtataaatgcacaagaa 7200 atgggatatg ccatcaccta tgtgccatta gtgagcatgt acagtatgccaaacactatt 7260 gttcacgttt ggaggaagta atgggggtgg gggagcaaca agggttataaccgtataccc 7320 agtgccttgg aagcgattgc aaacagtaaa gactgacatt gtgttctccctatgagggag 7380 gggccttggg ctgagcactt tgcaatgagc atttgctcat tgtgctggcaggttttatga 7440 taacttgacc caagctagag tcactggaga ggaaggaact tcaactgagaacatgcctga 7500 agaagatcag attataggca ggcctgtggg gcattttctt aattagtgattcatggggca 7560 gggcccagtc cattgttcgt ggtaccattt ctcaggcact attaaaaaaaaaaaaacagg 7620 ctgagcaagt gtcaaggagc aagtcagtga gcagcagccc taatgatctctgcatcagct 7680 cctgcctcca ggttcctacc ctatttgagt tcctgtccta gctccctacagtgatgaaca 7740 atgatgtgga agtataagcc aaataaatcc tttcttcccc aacttgctgttggtcatgat 7800 gtttcatcac agtgataata gtcctcatga agatgctggt gtttataacacctttggact 7860 aaattctgtt atctatagct gaggaaaatg gagcatagaa agtctccagactacaccaga 7920 gtgtaatctg ggcctgagct tagaatcaca cccacgtgca ctccactgccggggcttctt 7980 aaccggaaca cagttgtaaa agggaatttt ctgtttgttt ccattttgacatgtggactt 8040 taattgacga ttcatctgaa gctgaaaatg attttttttc caggtataacagcctcacta 8100 gattgacaga aaatgacttt tctggcctga gcagactgga gttactcatgctgcacagca 8160 atggcattca cagagtcagt gacaagacct tctcgggctt gcagtccttgcaggtgagat 8220 aggtagaggg tgatggaggc tgagaagaga ggtgcaactg tgggttatacccaaaagctg 8280 ctgattcccg tgggagacat tctataagca ttctataaac tagaggcagatatcaaggaa 8340 ggatttcaat tgtaatgcaa ttttatgaga aaatttgaat attaagaaaatgctggggaa 8400 aatgcttaca caattgcgag gacctaattt aggatctcca atagccacataaaaagcaca 8460 gcatggcggc agacacctgc aattcctgtc cctggaagca cctgttcagaatcccagaga 8520 ctcattggcc aaacactcta ttcaatcaat gaagtccata ttcagtgacaaaacttgact 8580 cagaaactaa tgtggaaagc atcaggaaga cagccaacat ctggtctctactcatgcatg 8640 aataagggat cccagagaga agggaagaaa aaggaaggaa ggaaggaaggaaggaaggaa 8700 ggaaggaagg aaggaaggaa ggaagagagg gaggaaagga gggagggaaggaaggaaagg 8760 gaaaggaaaa aagagatggg gagggaggga aggaaaggaa agggggagaaagaagagaag 8820 aaaggaaaat aaataaattt tcagggatta ttacaccttt aaattttatccataaaaggt 8880 catttccacc tgtttgtctg gaagtagagt gggatccctt atataagggcagtctttaac 8940 atagtagcat tttataaacc attacaaatt ttgagttttc tctactttttatcctctacc 9000 atcttcaaac tgaaactaca attattccca caaatgaaga aaatgctgtaagagttttca 9060 cacaccgaag tgggaaactt aaggattaga caagtctaac aatgagaatggggagaacaa 9120 aaagagactg cacagggagc cctttctctg cttataatct tgacacttgagaagctaatt 9180 gacgctgcat gactactcaa ctctttaagc aaacaatgct gttgttcatgaaaagcacaa 9240 taaagtacat atgtcccata atattcatca aaatttgcat gcagcacataatagcaatca 9300 aagcaataac acccactgtt cacagagact ttaaacatga aactggaactatgtctagtg 9360 ttttgactta gggtacatag tatgctgtgt ctgtatgtac caatgttgatttaggtcatc 9420 agacagcatt tggaacatgt atcttcagga ggaatcattc atgtatcctgcatgaaattc 9480 tccacctatg tttattctct tagccaggtt tttctctgat ggagaaacattgggtttgag 9540 gttttactcc caggtaacat ttagggaaaa gctgtctatg ttctcagtttggcttttatt 9600 tatgagggat gttggtattc cagaaaattc tcttttgaag agattacaatttaggtcaaa 9660 acagaaaaat atgtaaaaag ttattgtttt tattagtatt tcatgttcttttctttttta 9720 aaaatggtat gcttagaact aattaagatt agattagatt agattagaaaataatcagag 9780 agggatttga tgaatgctaa agcatcatga aaaattcaaa attttttgcttctaattcag 9840 aatcaattaa attcatatta ctataaaaga cagcacgcca gatgtgtgccagctgaggag 9900 tggataaact gtgtaacgtg agtgctatgt agaaacagaa aggagtgaagggttgatgtg 9960 cgctgcaaca tcttgaaaac attcggctac atgatggaag ccaggcacaaaaagccacat 10020 attgcatggt tatgtttata tgaaatgttt aaaatacatg gattcttagcaaacagagta 10080 agatgttact tagggtcagg aaaagattaa aaaaaaaaaa actattgatgtggaatgatc 10140 ttaatttggg gaaaagacaa tttcctaaga cgaaatagtt gaggtagatatagttatatc 10200 cctgtggata ttgtaataaa ccagcatgct gtgctctgag aagggcctaatgaaggggca 10260 ggaggaagtg aaatgagatg gtagaaagga aagtcatata ccatggcttctctcgtgggt 10320 ggaatctaga tatgttaata tattgacata aaggaaggaa ttgtttagggaaggatcaaa 10380 accaacagga gtgagggaga caataggaac caatgagagg caaagttcatggtcaatgtg 10440 tgtggagaca ccataataaa actccttttt tgtttgctaa ctaaaaccactaaaatctaa 10500 aaacaaaaca tttttgcaca agaattattt attattcaat aaagatgtttaaatggggga 10560 agttgaagtt cattgatagt ctcataaatc ttaaatgtat ttaaactgctttttacgttt 10620 tttattatta attactcttg ctgtcattat tatcatcatc attatcgtcatcatcatcac 10680 taatgctttt caccatacac aaatgtaggc agaagagtgt aatccacttagtgaggcaat 10740 cttggagagg gaaaggaagc ggatgcgggg cagaggcaca caggaggacagtgagaggga 10800 aatgaacaag aaaaaatgtg gacacatgca caaaaattcc atagtccactacattacttt 10860 gtattctaat attaagaaaa taataaaccc atttctgtgc acttatcacccaggctcaac 10920 agttatcttg gccacagatc ctgtctcact gcatcctgtc cacctgagtccacttagcgt 10980 tctgaatcca atccagggca tgatgcttac tcctacacag aactaaagattaaagagagt 11040 ttaaaagtaa ccatgacatc tctctgttcc tttagcgata agttcttaatatttatggct 11100 gcttgtgtat gttctaattt ctctaatatt gtcacattta gttggcaactactttgtttg 11160 aattgagttg gagttaaggt cccataggat taatctcaac atatttctatatttataaac 11220 ttttctctct ttgtgaaagt tcctttgaga aaacaaatat gcccatatctttctttacag 11280 gtcttaaaaa tgagctataa caaagtccaa ataattgaga aggatactttgtatggactc 11340 aggagcttga cccggttgca cctggatcac aacaacattg agtttatcaaccccgaggcg 11400 ttttacggac tcaccttgct ccgcttggta catctagaag gaaaccggctgacaaagctc 11460 catccagaca catttgtctc tttgagctat ctccagatat ttaaaacctccttcattaag 11520 nacctgtact tgtatgataa cttcattgac ctccctccca aaagaaatggtctcctctat 11580 gccaaaccta gaaagccttt acttgcatgg aaacccatgg acctgtgactgccatttaaa 11640 gtggttgtcc gagtggatgc agggaaaccc aggtaactat cttgtttgtttgtttctttt 11700 tttatarkac gtattttcct caatttcatt tagaatgata tcccaaaagtcccccataac 11760 ctccccccca cttccctacc tacccattcc cattttttgg ccctggcattcccctgtact 11820 ggggcatata aagtttgcgt gtccaatgga cctctctttc cagtgatggccaactaggcc 11880 atcttttgat acatatgcag ctagagtcaa gagctctggg gtactggttagttcataatg 11940 ttgttgcacc tacagggttg aa 11962 21 2828 PRT homo sapiens21 Met Pro Lys Arg Ala His Trp Gly Ala Leu Ser Val Val Leu Ile Leu 1 510 15 Leu Trp Gly His Pro Arg Val Ala Leu Ala Cys Pro His Pro Cys Ala 2025 30 Cys Tyr Val Pro Ser Glu Val His Cys Thr Phe Arg Ser Leu Ala Ser 3540 45 Val Pro Ala Gly Ile Ala Arg His Val Glu Arg Ile Asn Leu Gly Phe 5055 60 Asn Ser Ile Gln Ala Leu Ser Glu Thr Ser Phe Ala Gly Leu Thr Lys 6570 75 80 Leu Glu Leu Leu Met Ile His Gly Asn Glu Ile Pro Ser Ile Pro Asp85 90 95 Gly Ala Leu Arg Asp Leu Ser Ser Leu Gln Val Phe Lys Phe Ser Tyr100 105 110 Asn Lys Leu Arg Val Ile Thr Gly Gln Thr Leu Gln Gly Leu SerAsn 115 120 125 Leu Met Arg Leu His Ile Asp His Asn Lys Ile Glu Phe IleHis Pro 130 135 140 Gln Ala Phe Asn Gly Leu Thr Ser Leu Arg Leu Leu HisLeu Glu Gly 145 150 155 160 Asn Leu Leu His Gln Leu His Pro Ser Thr PheSer Thr Phe Thr Phe 165 170 175 Leu Asp Tyr Phe Arg Leu Ser Thr Ile ArgHis Leu Tyr Leu Ala Glu 180 185 190 Asn Met Val Arg Thr Leu Pro Ala SerMet Leu Arg Asn Met Pro Leu 195 200 205 Leu Glu Asn Leu Tyr Leu Gln GlyAsn Pro Trp Thr Cys Asp Cys Glu 210 215 220 Met Arg Trp Phe Leu Glu TrpAsp Ala Lys Ser Arg Gly Ile Leu Lys 225 230 235 240 Cys Lys Lys Asp LysAla Tyr Glu Gly Gly Gln Leu Cys Ala Met Cys 245 250 255 Phe Ser Pro LysLys Leu Tyr Lys His Glu Ile His Lys Leu Lys Asp 260 265 270 Met Thr CysLeu Lys Pro Ser Ile Glu Ser Pro Leu Arg Gln Asn Arg 275 280 285 Ser ArgSer Ile Glu Glu Glu Gln Glu Gln Glu Glu Asp Gly Gly Ser 290 295 300 GlnLeu Ile Leu Glu Lys Phe Gln Leu Pro Gln Trp Ser Ile Ser Leu 305 310 315320 Asn Met Thr Asp Glu His Gly Asn Met Val Asn Leu Val Cys Asp Ile 325330 335 Lys Lys Pro Met Asp Val Tyr Lys Ile His Leu Asn Gln Thr Asp Pro340 345 350 Pro Asp Ile Asp Ile Asn Ala Thr Val Ala Leu Asp Phe Glu CysPro 355 360 365 Met Thr Arg Glu Asn Tyr Glu Lys Leu Trp Lys Leu Ile AlaTyr Tyr 370 375 380 Ser Glu Val Pro Val Lys Leu His Arg Glu Leu Met LeuSer Lys Asp 385 390 395 400 Pro Arg Val Ser Tyr Gln Tyr Arg Gln Asp AlaAsp Glu Glu Ala Leu 405 410 415 Tyr Tyr Thr Gly Val Arg Ala Gln Ile LeuAla Glu Pro Glu Trp Val 420 425 430 Met Gln Pro Ser Ile Asp Ile Gln LeuAsn Arg Arg Gln Ser Thr Ala 435 440 445 Lys Lys Val Leu Leu Ser Tyr TyrThr Gln Tyr Ser Gln Thr Ile Ser 450 455 460 Thr Lys Asp Thr Arg Gln AlaArg Gly Arg Ser Trp Val Met Ile Glu 465 470 475 480 Pro Ser Gly Ala ValGln Arg Asp Gln Thr Val Leu Glu Gly Gly Pro 485 490 495 Cys Gln Leu SerCys Asn Val Lys Ala Ser Glu Ser Pro Ser Ile Phe 500 505 510 Trp Val LeuPro Asp Gly Ser Ile Leu Lys Ala Pro Met Asp Asp Pro 515 520 525 Asp SerLys Phe Ser Ile Leu Ser Ser Gly Trp Leu Arg Ile Lys Ser 530 535 540 MetGlu Pro Ser Asp Ser Gly Leu Tyr Gln Cys Ile Ala Gln Val Arg 545 550 555560 Asp Glu Met Asp Arg Met Val Tyr Arg Val Leu Val Gln Ser Pro Ser 565570 575 Thr Gln Pro Ala Glu Lys Asp Thr Val Thr Ile Gly Lys Asn Pro Gly580 585 590 Glu Ser Val Thr Leu Pro Cys Asn Ala Leu Ala Ile Pro Glu AlaHis 595 600 605 Leu Ser Trp Ile Leu Pro Asn Arg Arg Ile Ile Asn Asp LeuAla Asn 610 615 620 Thr Ser His Val Tyr Met Leu Pro Asn Gly Thr Leu SerIle Pro Lys 625 630 635 640 Val Gln Val Ser Asp Ser Gly Tyr Tyr Arg CysVal Ala Val Asn Gln 645 650 655 Gln Gly Ala Asp His Phe Thr Val Gly IleThr Val Thr Lys Lys Gly 660 665 670 Ser Gly Leu Pro Ser Lys Arg Gly ArgArg Pro Gly Ala Lys Ala Leu 675 680 685 Ser Arg Val Arg Glu Asp Ile ValGlu Asp Glu Gly Gly Ser Gly Met 690 695 700 Gly Asp Glu Glu Asn Thr SerArg Arg Leu Leu His Pro Lys Asp Gln 705 710 715 720 Glu Val Phe Leu LysThr Lys Asp Asp Ala Ile Asn Gly Asp Lys Lys 725 730 735 Ala Lys Lys GlyArg Arg Lys Leu Lys Leu Trp Lys His Ser Glu Lys 740 745 750 Glu Pro GluThr Asn Val Ala Glu Gly Arg Arg Val Phe Glu Ser Arg 755 760 765 Arg ArgIle Asn Met Ala Asn Lys Gln Ile Asn Pro Glu Arg Trp Ala 770 775 780 AspIle Leu Ala Lys Val Arg Gly Lys Asn Leu Pro Lys Gly Thr Glu 785 790 795800 Val Pro Pro Leu Ile Lys Thr Thr Ser Pro Pro Ser Leu Ser Leu Glu 805810 815 Val Thr Pro Pro Phe Pro Ala Val Ser Pro Pro Ser Ala Ser Pro Val820 825 830 Gln Thr Val Thr Ser Ala Glu Glu Ser Ser Ala Asp Val Pro LeuLeu 835 840 845 Gly Glu Glu Glu His Val Leu Gly Thr Ile Ser Ser Ala SerMet Gly 850 855 860 Leu Glu His Asn His Asn Gly Val Ile Leu Val Glu ProGlu Val Thr 865 870 875 880 Ser Thr Pro Leu Glu Glu Val Val Asp Asp LeuSer Glu Lys Thr Glu 885 890 895 Glu Ile Thr Ser Thr Glu Gly Asp Leu LysGly Thr Ala Ala Pro Thr 900 905 910 Leu Ile Ser Glu Pro Tyr Glu Pro SerPro Thr Leu His Thr Leu Asp 915 920 925 Thr Val Tyr Glu Lys Pro Thr HisGlu Glu Thr Ala Thr Glu Gly Trp 930 935 940 Ser Ala Ala Asp Val Gly SerSer Pro Glu Pro Thr Ser Ser Glu Tyr 945 950 955 960 Glu Pro Pro Leu AspAla Val Ser Leu Ala Glu Ser Glu Pro Met Gln 965 970 975 Tyr Phe Asp ProAsp Leu Glu Thr Lys Ser Gln Pro Asp Glu Asp Lys 980 985 990 Met Lys GluAsp Thr Phe Ala His Leu Thr Pro Thr Pro Thr Ile Trp 995 1000 1005 ValAsn Asp Ser Ser Thr Ser Gln Leu Phe Glu Asp Ser Thr Ile 1010 1015 1020Gly Glu Pro Gly Val Pro Gly Gln Ser His Leu Gln Gly Leu Thr 1025 10301035 Asp Asn Ile His Leu Val Lys Ser Ser Leu Ser Thr Gln Asp Thr 10401045 1050 Leu Leu Ile Lys Lys Gly Met Lys Glu Met Ser Gln Thr Leu Gln1055 1060 1065 Gly Gly Asn Met Leu Glu Gly Asp Pro Thr His Ser Arg SerSer 1070 1075 1080 Glu Ser Glu Gly Gln Glu Ser Lys Ser Ile Thr Leu ProAsp Ser 1085 1090 1095 Thr Leu Gly Ile Met Ser Ser Met Ser Pro Val LysLys Pro Ala 1100 1105 1110 Glu Thr Thr Val Gly Thr Leu Leu Asp Lys AspThr Thr Thr Val 1115 1120 1125 Thr Thr Thr Pro Arg Gln Lys Val Ala ProSer Ser Thr Met Ser 1130 1135 1140 Thr His Pro Ser Arg Arg Arg Pro AsnGly Arg Arg Arg Leu Arg 1145 1150 1155 Pro Asn Lys Phe Arg His Arg HisLys Gln Thr Pro Pro Thr Thr 1160 1165 1170 Phe Ala Pro Ser Glu Thr PheSer Thr Gln Pro Thr Gln Ala Pro 1175 1180 1185 Asp Ile Lys Ile Ser SerGln Val Glu Ser Ser Leu Val Pro Thr 1190 1195 1200 Ala Trp Val Asp AsnThr Val Asn Thr Pro Lys Gln Leu Glu Met 1205 1210 1215 Glu Lys Asn AlaGlu Pro Thr Ser Lys Gly Thr Pro Arg Arg Lys 1220 1225 1230 His Gly LysArg Pro Asn Lys His Arg Tyr Thr Pro Ser Thr Val 1235 1240 1245 Ser SerArg Ala Ser Gly Ser Lys Pro Ser Pro Ser Pro Glu Asn 1250 1255 1260 LysHis Arg Asn Ile Val Thr Pro Ser Ser Glu Thr Ile Leu Leu 1265 1270 1275Pro Arg Thr Val Ser Leu Lys Thr Glu Gly Pro Tyr Asp Ser Leu 1280 12851290 Asp Tyr Met Thr Thr Thr Arg Lys Ile Tyr Ser Ser Tyr Pro Lys 12951300 1305 Val Gln Glu Thr Leu Pro Val Thr Tyr Lys Pro Thr Ser Asp Gly1310 1315 1320 Lys Glu Ile Lys Asp Asp Val Ala Thr Asn Val Asp Lys HisLys 1325 1330 1335 Ser Asp Ile Leu Val Thr Gly Glu Ser Ile Thr Asn AlaIle Pro 1340 1345 1350 Thr Ser Arg Ser Leu Val Ser Thr Met Gly Glu PheLys Glu Glu 1355 1360 1365 Ser Ser Pro Val Gly Phe Pro Gly Thr Pro ThrTrp Asn Pro Ser 1370 1375 1380 Arg Thr Ala Gln Pro Gly Arg Leu Gln ThrAsp Ile Pro Val Thr 1385 1390 1395 Thr Ser Gly Glu Asn Leu Thr Asp ProPro Leu Leu Lys Glu Leu 1400 1405 1410 Glu Asp Val Asp Phe Thr Ser GluPhe Leu Ser Ser Leu Thr Val 1415 1420 1425 Ser Thr Pro Phe His Gln GluGlu Ala Gly Ser Ser Thr Thr Leu 1430 1435 1440 Ser Ser Ile Lys Val GluVal Ala Ser Ser Gln Ala Glu Thr Thr 1445 1450 1455 Thr Leu Asp Gln AspHis Leu Glu Thr Thr Val Ala Ile Leu Leu 1460 1465 1470 Ser Glu Thr ArgPro Gln Asn His Thr Pro Thr Ala Ala Arg Met 1475 1480 1485 Lys Glu ProAla Ser Ser Ser Pro Ser Thr Ile Leu Met Ser Leu 1490 1495 1500 Gly GlnThr Thr Thr Thr Lys Pro Ala Leu Pro Ser Pro Arg Ile 1505 1510 1515 SerGln Ala Ser Arg Asp Ser Lys Glu Asn Val Phe Leu Asn Tyr 1520 1525 1530Val Gly Asn Pro Glu Thr Glu Ala Thr Pro Val Asn Asn Glu Gly 1535 15401545 Thr Gln His Met Ser Gly Pro Asn Glu Leu Ser Thr Pro Ser Ser 15501555 1560 Asp Arg Asp Ala Phe Asn Leu Ser Thr Lys Leu Glu Leu Glu Lys1565 1570 1575 Gln Val Phe Gly Ser Arg Ser Leu Pro Arg Gly Pro Asp SerGln 1580 1585 1590 Arg Gln Asp Gly Arg Val His Ala Ser His Gln Leu ThrArg Val 1595 1600 1605 Pro Ala Lys Pro Ile Leu Pro Thr Ala Thr Val ArgLeu Pro Glu 1610 1615 1620 Met Ser Thr Gln Ser Ala Ser Arg Tyr Phe ValThr Ser Gln Ser 1625 1630 1635 Pro Arg His Trp Thr Asn Lys Pro Glu IleThr Thr Tyr Pro Ser 1640 1645 1650 Gly Ala Leu Pro Glu Asn Lys Gln PheThr Thr Pro Arg Leu Ser 1655 1660 1665 Ser Thr Thr Ile Pro Leu Pro LeuHis Met Ser Lys Pro Ser Ile 1670 1675 1680 Pro Ser Lys Phe Thr Asp ArgArg Thr Asp Gln Phe Asn Gly Tyr 1685 1690 1695 Ser Lys Val Phe Gly AsnAsn Asn Ile Pro Glu Ala Arg Asn Pro 1700 1705 1710 Val Gly Lys Pro ProSer Pro Arg Ile Pro His Tyr Ser Asn Gly 1715 1720 1725 Arg Leu Pro PhePhe Thr Asn Lys Thr Leu Ser Phe Pro Gln Leu 1730 1735 1740 Gly Val ThrArg Arg Pro Gln Ile Pro Thr Ser Pro Ala Pro Val 1745 1750 1755 Met ArgGlu Arg Lys Val Ile Pro Gly Ser Tyr Asn Arg Ile His 1760 1765 1770 SerHis Ser Thr Phe His Leu Asp Phe Gly Pro Pro Ala Pro Pro 1775 1780 1785Leu Leu His Thr Pro Gln Thr Thr Gly Ser Pro Ser Thr Asn Leu 1790 17951800 Gln Asn Ile Pro Met Val Ser Ser Thr Gln Ser Ser Ile Ser Phe 18051810 1815 Ile Thr Ser Ser Val Gln Ser Ser Gly Ser Phe His Gln Ser Ser1820 1825 1830 Ser Lys Phe Phe Ala Gly Gly Pro Pro Ala Ser Lys Phe TrpSer 1835 1840 1845 Leu Gly Glu Lys Pro Gln Ile Leu Thr Lys Ser Pro GlnThr Val 1850 1855 1860 Ser Val Thr Ala Glu Thr Asp Thr Val Phe Pro CysGlu Ala Thr 1865 1870 1875 Gly Lys Pro Lys Pro Phe Val Thr Trp Thr LysVal Ser Thr Gly 1880 1885 1890 Ala Leu Met Thr Pro Asn Thr Arg Ile GlnArg Phe Glu Val Leu 1895 1900 1905 Lys Asn Gly Thr Leu Val Ile Arg LysVal Gln Val Gln Asp Arg 1910 1915 1920 Gly Gln Tyr Met Cys Thr Ala SerAsn Leu His Gly Leu Asp Arg 1925 1930 1935 Met Val Val Leu Leu Ser ValThr Val Gln Gln Pro Gln Ile Leu 1940 1945 1950 Ala Ser His Tyr Gln AspVal Thr Val Tyr Leu Gly Asp Thr Ile 1955 1960 1965 Ala Met Glu Cys LeuAla Lys Gly Thr Pro Ala Pro Gln Ile Ser 1970 1975 1980 Trp Ile Phe ProAsp Arg Arg Val Trp Gln Thr Val Ser Pro Val 1985 1990 1995 Glu Ser ArgIle Thr Leu His Glu Asn Arg Thr Leu Ser Ile Lys 2000 2005 2010 Glu AlaSer Phe Ser Asp Arg Gly Val Tyr Lys Cys Val Ala Ser 2015 2020 2025 AsnAla Ala Gly Ala Asp Ser Leu Ala Ile Arg Leu His Val Ala 2030 2035 2040Ala Leu Pro Pro Val Ile His Gln Glu Lys Leu Glu Asn Ile Ser 2045 20502055 Leu Pro Pro Gly Leu Ser Ile His Ile His Cys Thr Ala Lys Ala 20602065 2070 Ala Pro Leu Pro Ser Val Arg Trp Val Leu Gly Asp Gly Thr Gln2075 2080 2085 Ile Arg Pro Ser Gln Phe Leu His Gly Asn Leu Phe Val PhePro 2090 2095 2100 Asn Gly Thr Leu Tyr Ile Arg Asn Leu Ala Pro Lys AspSer Gly 2105 2110 2115 Arg Tyr Glu Cys Val Ala Ala Asn Leu Val Gly SerAla Arg Arg 2120 2125 2130 Thr Val Gln Leu Asn Val Gln Arg Ala Ala AlaAsn Ala Arg Ile 2135 2140 2145 Thr Gly Thr Ser Pro Arg Arg Thr Asp ValArg Tyr Gly Gly Thr 2150 2155 2160 Leu Lys Leu Asp Cys Ser Ala Ser GlyAsp Pro Trp Pro Arg Ile 2165 2170 2175 Leu Trp Arg Leu Pro Ser Lys ArgMet Ile Asp Ala Leu Phe Ser 2180 2185 2190 Phe Asp Ser Arg Ile Lys ValPhe Ala Asn Gly Thr Leu Val Val 2195 2200 2205 Lys Ser Val Thr Asp LysAsp Ala Gly Asp Tyr Leu Cys Val Ala 2210 2215 2220 Arg Asn Lys Val GlyAsp Asp Tyr Val Val Leu Lys Val Asp Val 2225 2230 2235 Val Met Lys ProAla Lys Ile Glu His Lys Glu Glu Asn Asp His 2240 2245 2250 Lys Val PheTyr Gly Gly Asp Leu Lys Val Asp Cys Val Ala Thr 2255 2260 2265 Gly LeuPro Asn Pro Glu Ile Ser Trp Ser Leu Pro Asp Gly Ser 2270 2275 2280 LeuVal Asn Ser Phe Met Gln Ser Asp Asp Ser Gly Gly Arg Thr 2285 2290 2295Lys Arg Tyr Val Val Phe Asn Asn Gly Thr Leu Tyr Phe Asn Glu 2300 23052310 Val Gly Met Arg Glu Glu Gly Asp Tyr Thr Cys Phe Ala Glu Asn 23152320 2325 Gln Val Gly Lys Asp Glu Met Arg Val Arg Val Lys Val Val Thr2330 2335 2340 Ala Pro Ala Thr Ile Arg Asn Lys Thr Tyr Leu Ala Val GlnVal 2345 2350 2355 Pro Tyr Gly Asp Val Val Thr Val Ala Cys Glu Ala LysGly Glu 2360 2365 2370 Pro Met Pro Lys Val Thr Trp Leu Ser Pro Thr AsnLys Val Ile 2375 2380 2385 Pro Thr Ser Ser Glu Lys Tyr Gln Ile Tyr GlnAsp Gly Thr Leu 2390 2395 2400 Leu Ile Gln Lys Ala Gln Arg Ser Asp SerGly Asn Tyr Thr Cys 2405 2410 2415 Leu Val Arg Asn Ser Ala Gly Glu AspArg Lys Thr Val Trp Ile 2420 2425 2430 His Val Asn Val Gln Pro Pro LysIle Asn Gly Asn Pro Asn Pro 2435 2440 2445 Ile Thr Thr Val Arg Glu IleAla Ala Gly Gly Ser Arg Lys Leu 2450 2455 2460 Ile Asp Cys Lys Ala GluGly Ile Pro Thr Pro Arg Val Leu Trp 2465 2470 2475 Ala Phe Pro Glu GlyVal Val Leu Pro Ala Pro Tyr Tyr Gly Asn 2480 2485 2490 Arg Ile Thr ValHis Gly Asn Gly Ser Leu Asp Ile Arg Ser Leu 2495 2500 2505 Arg Lys SerAsp Ser Val Gln Leu Val Cys Met Ala Arg Asn Glu 2510 2515 2520 Gly GlyGlu Ala Arg Leu Ile Val Gln Leu Thr Val Leu Glu Pro 2525 2530 2535 MetGlu Lys Pro Ile Phe His Asp Pro Ile Ser Glu Lys Ile Thr 2540 2545 2550Ala Met Ala Gly His Thr Ile Ser Leu Asn Cys Ser Ala Ala Gly 2555 25602565 Thr Pro Thr Pro Ser Leu Val Trp Val Leu Pro Asn Gly Thr Asp 25702575 2580 Leu Gln Ser Gly Gln Gln Leu Gln Arg Phe Tyr His Lys Ala Asp2585 2590 2595 Gly Met Leu His Ile Ser Gly Leu Ser Ser Val Asp Ala GlyAla 2600 2605 2610 Tyr Arg Cys Val Ala Arg Asn Ala Ala Gly His Thr GluArg Leu 2615 2620 2625 Val Ser Leu Lys Val Gly Leu Lys Pro Glu Ala AsnLys Gln Tyr 2630 2635 2640 His Asn Leu Val Ser Ile Ile Asn Gly Glu ThrLeu Lys Leu Pro 2645 2650 2655 Cys Thr Pro Pro Gly Ala Gly Gln Gly ArgPhe Ser Trp Thr Leu 2660 2665 2670 Pro Asn Gly Met His Leu Glu Gly ProGln Thr Leu Gly Arg Val 2675 2680 2685 Ser Leu Leu Asp Asn Gly Thr LeuThr Val Arg Glu Ala Ser Val 2690 2695 2700 Phe Asp Arg Gly Thr Tyr ValCys Arg Met Glu Thr Glu Tyr Gly 2705 2710 2715 Pro Ser Val Thr Ser IlePro Val Ile Val Ile Ala Tyr Pro Pro 2720 2725 2730 Arg Ile Thr Ser GluPro Thr Pro Val Ile Tyr Thr Arg Pro Gly 2735 2740 2745 Asn Thr Val LysLeu Asn Cys Met Ala Met Gly Ile Pro Lys Ala 2750 2755 2760 Asp Ile ThrTrp Glu Leu Pro Asp Lys Ser His Leu Lys Ala Gly 2765 2770 2775 Val GlnAla Arg Leu Tyr Gly Asn Arg Phe Leu His Pro Gln Gly 2780 2785 2790 SerLeu Thr Ile Gln His Ala Thr Gln Arg Asp Ala Gly Phe Tyr 2795 2800 2805Lys Cys Met Ala Lys Asn Ile Leu Gly Ser Asp Ser Lys Thr Thr 2810 28152820 Tyr Ile His Val Phe 2825 22 9645 DNA homo sapiens misc_feature(1)..(9645) ′n′ can be any nucleotide ′a′, ′c′, ′g′ or ′t′. 22atgcccaagc gcgcgcactg gggggccctc tccgtggtgc tgatcctgct ttggggccat 60ccgcgagtgg cgctggcctg cccgcatcct tgtgcctgct acgtccccag cgaggtccac 120tgcacgttcc gatccctggc ttccgtgccc gctggcattg ctagacacgt ggaaagaatc 180aatttggggt ttaatagcat acaggccctg tcagaaacct catttgcagg actgaccaag 240ttggagctac ttatgattca cggcaatgag atcccaagca tccccgatgg agctttaaga 300gacctcagct ctcttcaggt tttcaagttc agctacaaca agctgagagt gatcacagga 360cagaccctcc agggtctctc taacttaatg aggctgcaca ttgaccacaa caagatcgag 420tttatccacc ctcaagcttt caacggctta acgtctctga ggctactcca tttggaagga 480aatctcctcc accagctgca ccccagcacc ttctccacgt tcacattttt ggattatttc 540agactctcca ccataaggca cctctactta gcagagaaca tggttagaac tcttcctgcc 600agcatgcttc ggaacatgcc gcttctggag aatctttact tgcagggaaa tccgtggacc 660tgcgattgtg agatgagatg gtttttggaa tgggatgcaa aatccagagg aattctgaag 720tgtaaaaagg acaaagctta tgaaggcggt cagttgtgtg caatgtgctt cagtccaaag 780aagttgtaca aacatgagat acacaagctg aaggacatga cttgtctgaa gccttcaata 840gagtcccctc tgagacagaa caggagcagg agtattgagg aggagcaaga acaggaagag 900gatggtggca gccagctcat cctggagaaa ttccaactgc cccagtggag catctctttg 960aatatgaccg acgagcacgg gaacatggtg aacttggtct gtgacatcaa gaaaccaatg 1020gatgtgtaca agattcactt gaaccaaacg gatcctccag atattgacat aaatgcaaca 1080gttgccttgg actttgagtg tccaatgacc cgagaaaact atgaaaagct atggaaattg 1140atagcatact acagtgaagt tcccgtgaag ctacacagag agctcatgct cagcaaagac 1200cccagagtca gctaccagta caggcaggat gctgatgagg aagctcttta ctacacaggt 1260gtgagagccc agattcttgc agaaccagaa tgggtcatgc agccatccat agatatccag 1320ctgaaccgac gtcagagtac ggccaagaag gtgctacttt cctactacac ccagtattct 1380caaacaatat ccaccaaaga tacaaggcag gctcggggca gaagctgggt aatgattgag 1440cctagtggag ctgtgcaaag agatcagact gtcctggaag ggggtccatg ccagttgagc 1500tgcaacgtga aagcttctga gagtccatct atcttctggg tgcttccaga tggctccatc 1560ctgaaagcgc ccatggatga cccagacagc aagttctcca ttctcagcag tggctggctg 1620aggatcaagt ccatggagcc atctgactca ggcttgtacc agtgcattgc tcaagtgagg 1680gatgaaatgg accgcatggt atatagggta cttgtgcagt ctccctccac tcagccagcc 1740gagaaagaca cagtgacaat tggcaagaac ccaggggagt cggtgacatt gccttgcaat 1800gctttagcaa tacccgaagc ccaccttagc tggattcttc caaacagaag gataattaat 1860gatttggcta acacatcaca tgtatacatg ttgccaaatg gaactctttc catcccaaag 1920gtccaagtca gtgatagtgg ttactacaga tgtgtggctg tcaaccagca aggggcagac 1980cattttacgg tgggaatcac agtgaccaag aaagggtctg gcttgccatc caaaagaggc 2040agacgcccag gtgcaaaggc tctttccaga gtcagagaag acatcgtgga ggatgaaggg 2100ggctcgggca tgggagatga agagaacact tcaaggagac ttctgcatcc aaaggaccaa 2160gaggtgttcc tcaaaacaaa ggatgatgcc atcaatggag acaagaaagc caagaaaggg 2220agaagaaagc tgaaactctg gaagcattcg gaaaaagaac cagagaccaa tgttgcagaa 2280ggtcgcagag tgtttgaatc tagacgaagg ataaacatgg caaacaaaca gattaatccg 2340gagcgctggg ctgatatttt agccaaagtc cgtgggaaaa atctccctaa gggcacagaa 2400gtacccccgt tgattaaaac cacaagtcct ccatccttga gcctagaagt cacaccacct 2460tttcctgctg tttctccccc ctcagcatct cctgtgcaga cagtaaccag tgctgaagaa 2520tcctcagcag atgtacctct acttggtgaa gaagagcacg ttttgggtac catttcctca 2580gccagcatgg ggctagaaca caaccacaat ggagttattc ttgttgaacc tgaagtaaca 2640agcacacctc tggaggaagt tgttgatgac ctttctgaga agactgagga gataacttcc 2700actgaaggag acctgaaggg gacagcagcc cctacactta tatctgagcc ttatgaacca 2760tctcctactc tgcacacatt agacacagtc tatgaaaagc ccacccatga agagacggca 2820acagagggtt ggtctgcagc agatgttgga tcgtcaccag agcccacatc cagtgagtat 2880gagcctccat tggatgctgt ctccttggct gagtctgagc ccatgcaata ctttgaccca 2940gatttggaga ctaagtcaca accagatgag gataagatga aagaagacac ctttgcacac 3000cttactccaa cccccaccat ctgggttaat gactccagta catcacagtt atttgaggat 3060tctactatag gggaaccagg tgtcccaggc caatcacatc tacaaggact gacagacaac 3120atccaccttg tgaaaagtag tctaagcact caagacacct tactgattaa aaagggtatg 3180aaagagatgt ctcagacact acagggagga aatatgctag agggagaccc cacacactcc 3240agaagttctg agagtgaggg ccaagagagc aaatccatca ctttgcctga ctccacactg 3300ggtataatga gcagtatgtc tccagttaag aagcctgcgg aaaccacagt tggtaccctc 3360ctagacaaag acaccacaac agtaacaaca acaccaaggc aaaaagttgc tccgtcatcc 3420accatgagca ctcacccttc tcgaaggaga cccaacggga gaaggagatt acgccccaac 3480aaattccgcc accggcacaa gcaaacccca cccacaactt ttgccccatc agagactttt 3540tctactcaac caactcaagc acctgacatt aagatttcaa gtcaagtgga gagttctctg 3600gttcctacag cttgggtgga taacacagtt aataccccca aacagttgga aatggagaag 3660aatgcagaac ccacatccaa gggaacacca cggagaaaac acgggaagag gccaaacaaa 3720catcgatata ccccttctac agtgagctca agagcgtccg gatccaagcc cagcccttct 3780ccagaaaata aacatagaaa cattgttact cccagttcag aaactatact tttgcctaga 3840actgtttctc tgaaaactga gggcccttat gattccttag attacatgac aaccaccaga 3900aaaatatatt catcttaccc taaagtccaa gagacacttc cagtcacata taaacccaca 3960tcagatggaa aagaaattaa ggatgatgtt gccacaaatg ttgacaaaca taaaagtgac 4020attttagtca ctggtgaatc aattactaat gccataccaa cttctcgctc cttggtctcc 4080actatgggag aatttaagga agaatcctct cctgtaggct ttccaggaac tccaacctgg 4140aatccctcaa ggacggccca gcctgggagg ctacagacag acatacctgt taccacttct 4200ggggaaaatc ttacagaccc tccccttctt aaagagcttg aggatgtgga tttcacttcc 4260gagtttttgt cctctttgac agtctccaca ccatttcacc aggaagaagc tggttcttcc 4320acaactctct caagcataaa agtggaggtg gcttcaagtc aggcagaaac caccaccctt 4380gatcaagatc atcttgaaac cactgtggct attctccttt ctgaaactag accacagaat 4440cacaccccta ctgctgcccg gatgaaggag ccagcatcct cgtccccatc cacaattctc 4500atgtctttgg gacaaaccac caccactaag ccagcacttc ccagtccaag aatatctcaa 4560gcatctagag attccaagga aaatgttttc ttgaattatg tggggaatcc agaaacagaa 4620gcaaccccag tcaacaatga aggaacacag catatgtcag ggccaaatga attatcaaca 4680ccctcttccg accgggatgc atttaacttg tctacaaagc tggaattgga aaagcaagta 4740tttggtagta ggagtctacc acgtggccca gatagccaac gccaggatgg aagagttcat 4800gcttctcatc aactaaccag agtccctgcc aaacccatcc taccaacagc aacagtgagg 4860ctacctgaaa tgtccacaca aagcgcttcc agatactttg taacttccca gtcacctcgt 4920cactggacca acaaaccgga aataactaca tatccttctg gggctttgcc agagaacaaa 4980cagtttacaa ctccaagatt atcaagtaca acaattcctc tcccattgca catgtccaaa 5040cccagcattc ctagtaagtt tactgaccga agaactgacc aattcaatgg ttactccaaa 5100gtgtttggaa ataacaacat ccctgaggca agaaacccag ttggaaagcc tcccagtcca 5160agaattcctc attattccaa tggaagactc cctttcttta ccaacaagac tctttctttt 5220ccacagttgg gagtcacccg gagaccccag atacccactt ctcctgcccc agtaatgaga 5280gagagaaaag ttattccagg ttcctacaac aggatacatt cccatagcac cttccatctg 5340gactttggcc ctccggcacc tccgttgttg cacactccgc agaccacggg atcaccctca 5400actaacttac agaatatccc tatggtctct tccacccaga gttctatctc ctttataaca 5460tcttctgtcc agtcctcagg aagcttccac cagagcagct caaagttctt tgcaggagga 5520cctcctgcat ccaaattctg gtctcttggg gaaaagcccc aaatcctcac caagtcccca 5580cagactgtgt ccgtcaccgc tgagacagac actgtgttcc cctgtgaggc aacaggaaaa 5640ccaaagcctt tcgttacttg gacaaaggtt tccacaggag ctcttatgac tccgaatacc 5700aggatacaac ggtttgaggt tctcaagaac ggtaccttag tgatacggaa ggttcaagta 5760caagatcgag gccagtatat gtgcaccgcc agcaacctgc acggcctgga caggatggtg 5820gtcttgcttt cggtcaccgt gcagcaacct caaatcctag cctcccacta ccaggacgtc 5880actgtctacc tgggagacac cattgcaatg gagtgtctgg ccaaagggac cccagccccc 5940caaatttcct ggatcttccc tgacaggagg gtgtggcaaa ctgtgtcccc cgtggagagc 6000cgcatcaccc tgcacgaaaa ccggaccctt tccatcaagg aggcgtcctt ctcagacaga 6060ggcgtctata agtgcgtggc cagcaatgca gccggggcgg acagcctggc catccgcctg 6120cacgtggcgg cactgccccc cgttatccac caggagaagc tggagaacat ctcgctgccc 6180ccggggctca gcattcacat tcactgcact gccaaggctg cgcccctgcc cagcgtgcgc 6240tgggtgctcg gggacggtac ccagatccgc ccctcgcagt tcctccacgg gaacttgttt 6300gttttcccca acgggacgct ctacatccgc aacctcgcgc ccaaggacag cgggcgctat 6360gagtgcgtgg ccgccaacct ggtaggctcc gcgcgcagga cggtgcagct gaacgtgcag 6420cgtgcagcag ccaacgcgcg catcacgggc acctccccgc ggaggacgga cgtcaggtac 6480ggaggaaccc tcaagctgga ctgcagcgcc tcgggggacc cctggccgcg catcctctgg 6540aggctgccgt ccaagaggat gatcgacgcg ctcttcagtt ttgatagcag aatcaaggtg 6600tttgccaatg ggaccctggt ggtgaaatca gtgacggaca aagatgccgg agattacctg 6660tgcgtagctc gaaataaggt tggtgatgac tacgtggtgc tcaaagtgga tgtggtgatg 6720aaaccggcca agattgaaca caaggaggag aacgaccaca aagtcttcta cgggggtgac 6780ctgaaagtgg actgtgtggc caccgggctt cccaatcccg agatctcctg gagcctccca 6840gacgggagtc tggtgaactc cttcatgcag tcggatgaca gcggtggacg caccaagcgc 6900tatgtcgtct tcaacaatgg gacactctac tttaacgaag tggggatgag ggaggaagga 6960gactacacct gctttgctga aaatcaggtc gggaaggacg agatgagagt cagagtcaag 7020gtggtgacag cgcccgccac catccggaac aagacttact tggcggttca ggtgccctat 7080ggagacgtgg tcactgtagc ctgtgaggcc aaaggagaac ccatgcccaa ggtgacttgg 7140ttgtccccaa ccaacaaggt gatccccacc tcctctgaga agtatcagat ataccaagat 7200ggcactctcc ttattcagaa agcccagcgt tctgacagcg gcaactacac ctgcctggtc 7260aggaacagcg cgggagagga taggaagacg gtgtggattc acgtcaacgt ccagccaccc 7320aagatcaacg gtaaccccaa ccccatcacc accgtgcggg agatagcagc cgggggcagt 7380cggaaactga ttgactgcaa agctgaaggc atccccaccc cgagggtgtt atgggctttt 7440cccgagggtg tggttctgcc agctccatac tatggaaacc ggatcactgt ccatggcaac 7500ggttccctgg acatcaggag tttgaggaag agcgactccg tccagctggt atgcatggca 7560cgcaacgagg gaggggaggc gaggttgatc gtgcagctca ctgtcctgga gcccatggag 7620aaacccatct tccacgaccc gatcagcgag aagatcacgg ccatggcggg ccacaccatc 7680agcctcaact gctctgccgc ggggaccccg acacccagcc tggtgtgggt ccttcccaat 7740ggcaccgatc tgcagagtgg acagcagctg cagcgcttct accacaaggc tgacggcatg 7800ctacacatta gcggtctctc ctcggtggac gctggggcct accgctgcgt ggcccgcaat 7860gccgctggcc acacggagag gctggtctcc ctgaaggtgg gactgaagcc agaagcaaac 7920aagcagtatc ataacctggt cagcatcatc aatggtgaga ccctgaagct cccctgcacc 7980cctcccgggg ctgggcaggg acgtttctcc tggacgctcc ccaatggcat gcatctggag 8040ggcccccaaa ccctgggacg cgtttctctt ctggacaatg gcaccctcac ggttcgtgag 8100gcctcggtgt ttgacagggg tacctatgta tgcaggatgg agacggagta cggcccttcg 8160gtcaccagca tccccgtgat tgtgatcgcc tatcctcccc ggatcaccag cgagcccacc 8220ccggtcatct acacccggcc cgggaacacc gtgaaactga actgcatggc tatggggatt 8280cccaaagctg acatcacgtg ggagttaccg gataagtcgc atctgaaggc aggggttcag 8340gctcgtctgt atggaaacag atttcttcac ccccagggat cactgaccat ccagcatgcc 8400acacagagag atgccggctt ctacaagtgc atggcaaaaa acattctcgg cagtgactcc 8460aaaacaactt acatccacgt cttctgaaat gtggattcca gaatgattgc ttaggaactg 8520acaacaaagc ggggtttgta agggaagcca ggttggggaa taggagctct taaataatgt 8580gtcacagtgc atggtggcct ctggtgggtt tcaagttgag gttgatcttg atctacaatt 8640gttgggaaaa ggaagcaatg cagacacgag aaggagggct cagccttgct gagacacttt 8700cttttgtgtt tacatcatgc caggggcttc attcagggtg tctgtgctct gactgcaatt 8760tttcttcttt tgcaaatgcc actcgactgc cttcataagc gtccatagga tatctgagga 8820acattcatca aaaataagcc atagacatga acaacacctc actaccccat tgaagacgca 8880tcacctagtt aacctgctgc agtttttaca tgatagactt tgttccagat tgacaagtca 8940tctttcagtt atttcctctg tcacttcaaa actccagctt gcccaataag gatttagaac 9000cagagtgact gatatatata tatatatttt aattcagagt tacatacata cagctaccat 9060tttatatgaa aaaagaaaaa catttcttcc tggaactcac tttttatata atgttttata 9120tatatatttt ttcctttcaa atcagacgat gagactagaa ggagaaatac tttctgtctt 9180attaaaatta ataaattatt ggtctttaca agacttggat acattacagc agacatggaa 9240atataatttt aaaaaatttc tctccaacct ccttcaaatt cagtcaccac tgttatatta 9300ccttctccag gaaccctcca gtggggaagg ctgcgatatt agatttcctt gtatgcaaag 9360tttttgttga aagctgtgct cagaggaggt gagaggagag gaaggagaaa actgcatcat 9420aactttacag aattgaatct agagtcttcc ccgaaaagcc cagaaacttc tctgcagtat 9480ctggcttgtc catctggtct aaggtggctg cttcttcccc agccatgagt cagtttgtgc 9540ccatgaataa tacacgacct gttatttcca tgactgcttt actgtatttt taaggtcaat 9600atactgtaca tttgataata aaataatatt ctcccaaaaa aaaaa 9645 23 21 DNAArtificial Sequence primer 23 gcactgaact gctctgtgga t 21 24 23 DNAArtificial Sequence primer 24 ccacagaagt aaggttcctt cac 23 25 6 PRT homosapiens 25 Lys Cys Lys Lys Asp Arg 1 5

1. A composition comprising an isolated polypeptide, wherein thepolypeptide is identified as Adlican or a functional portion thereof ora polypeptide which is at least substantially homologous or identicalthereto and a physiologically acceptable excipient.
 2. The compositionaccording to claim 1, wherein the polypeptide is a human Adlican or afunctional portion thereof.
 3. The composition according to claim 2,wherein the functional portion comprises a polypeptide having amolecular weight of 10 kD to 30 kD.
 4. The isolated polypeptideaccording to claim 1, wherein the the functional portion comprises apolypeptide having a molecular weight of about 25 kD.
 5. A compositioncomprising one or more isolated polypeptides according to claim
 1. 6. Anantibody elicited by a polypeptide according to claim 1 or a functionalportion thereof.
 7. A composition comprising the antibody according toclaim 6 or a functional portion thereof.
 8. A method for treating orpreventing osteoporosis, or for fracture healing, bone enlongation, orperiodontosis in a subject, comprising administering to the subject aneffective amount of the isolated polypeptide according to claim
 1. 9. Amethod of treating or preventing osteoarthritis, osteopetrosis, orosteosclerosis, comprising administering to a subject an effectiveamount of a chemical or neutralizing monoclonal antibodies which inhibitthe activity of the polypeptide according to claim
 1. 10. A compositioncomprising an isolated nucleic acid molecule encoding the polypeptideaccording to claim 1 and a physiologically acceptable excipient.
 11. Acomposition comprising a vector comprising an isolated nucleic acidmolecule encoding the polypeptide according to claim 1 and aphysiologically acceptable excipient.
 12. A method for preventing,treating or controlling osteoporosis, or for fracture healing, boneenlongation or osteopenia, periodontosis, or low bone density or otherconditions involving mechanical stress or a lack thereof in a subject,comprising administering to the subject an effective amount of acomposition as claimed in claim
 11. 13. A method for preventing,treating or controlling osteoporosis, or for fracture healing, boneenlongation or osteopenia, periodontosis, bone fractures or low bonedensity or other factors causing or contributing to osteoporosis orsymptoms thereof or other conditions involving mechanical stress or alack thereof in a subject, comprising administering the vector asclaimed in claim 12 to the subject.
 14. A method for preventing,treating or controlling osteoporosis, or for fracture healing, boneenlongation or osteopenia, periodontosis, bone fractures or low bonedensity or other factors causing or contributing to osteoporosis orsymptoms thereof or other conditions involving mechanical stress or alack thereof in a subject, comprising administering an isolated nucleicacid molecule encoding the polypeptide according to claim 1, or afunctional portion thereof or a polypeptide comprising an expressionproduct of the gene or functional portion of the polypeptide or anantibody to the polypeptide or a functional portion of the antibody.